2-(2-hydroxy-2-phenylethyl)-3-[(phenylmethyl)oxy]-4H-pyran-4-one of the formula P-3 and/or 2-[(E)-2-phenylethenyl]-3-[(phenylmethyl)oxy]-4H-Pyran-4-one of the formula P-4

ABSTRACT

The compounds are intermediates in the preparation of therapeutic agents useful in the treatment of viral infections, particularly HIV infection. The compounds are 2-(2-hydroxy-2-phenylethyl)-3-[(phenylmethyl)oxy]-4H-pyran-4-one of the formula P-3 and/or 2-[(E)-2-phenylethenyl]-3-[(phenylmethyl)oxy]-4H-pyran-4-one of the formula P-4.

CROSS REFERENCE TO RELATED APPLICATIONS

This application is a divisional of Ser. No. 14/044,285 filed Oct. 2,2013, now U.S. Pat. No. 8,765,965, which is a divisional of Ser. No.13/054,847 filed Apr. 8, 2011, now U.S. Pat. No. 8,580,967, which is a371 of PCT/US2009/051499 filed Jul. 23, 2009, which claims benefit ofprovisional application No. 61/083,621 filed Jul. 25, 2008.

BACKGROUND OF THE INVENTION

The human immunodeficiency virus (“HIV”) is the causative agent foracquired immunodeficiency syndrome (“AIDS”), a disease characterized bythe destruction of the immune system, particularly of CD4⁺ T-cells, withattendant susceptibility to opportunistic infections, and its precursorAIDS-related complex (“ARC”), a syndrome characterized by symptoms suchas persistent generalized lymphadenopathy, fever and weight loss. HIV isa retrovirus; the conversion of its RNA to DNA is accomplished throughthe action of the enzyme reverse transcriptase. Compounds that inhibitthe function of reverse transcriptase inhibit replication of HIV ininfected cells. Such compounds are useful in the prevention or treatmentof HIV infection in humans.

A required step in HIV replication in human T-cells is the insertion byvirally-encoded integrase of proviral DNA into the host cell genome.Integration is believed to be mediated by integrase in a processinvolving assembly of a stable nucleoprotein complex with viral DNAsequences, cleavage of two nucleotides from the 3′ termini of the linearproviral DNA and covalent joining of the recessed 3′ OH termini of theproviral DNA at a staggered cut made at the host target site. The repairsynthesis of the resultant gap may be accomplished by cellular enzymes.

There is continued need to find new therapeutic agents to treat humandiseases. HIV integrase is an attractive target for the discovery of newtherapeutics due to its important role in viral infections, particularlyHIV infections. Integrase inhibitors are disclosed in WO2006/116724. Thecompounds of the present invention are designed to deliver activetherapeutic agents.

SUMMARY OF THE INVENTION

The present invention features compounds that are prodrugs of HIVintegrase inhibitors and therefore are useful in the inhibition of HIVreplication, the prevention and/or treatment of infection by HIV, and inthe treatment of AIDS and/or ARC. The present invention features acompound of formula (I):

wherein:R¹ is C₁-C₈alkyl, C₆-C₁₀aryl or LR²;L is alkylene;R² isa) hydroxy;b) alkoxy;c) OR³ wherein R³ is P(O)(OH)₂, alkoxy, or alkylene-alkoxy;d) heterocyclyl optionally substituted with oxo or C₁-C₈alkyl;e) C(O)OR⁴ wherein R⁴ is H, C₁-C₈alkyl, or XR⁵ wherein X is alkylene andR⁵ is C₆-C₁₀aryl, heterocyclyl, or NR⁶R⁷ wherein R⁶ and R⁷ areindependently selected from the group consisting of H and C₁-C₈alkyl;f) NR⁶R⁷;g) C(O)NR⁸R⁹ wherein R⁸ and R⁹ are independently selected from the groupconsisting of H and XR⁵; orh) C(O)R¹⁰ wherein R¹⁰ is heterocyclyl optionally substituted with XR¹¹wherein R¹¹ is heterocyclyl;or a pharmaceutically acceptable salt thereof.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1: Plasma concentrations of(3S,11aR)—N-[(2,4-Difluorophenyl)methyl]-6-hydroxy-3-methyl-5,7-dioxo-2,3,5,7,11,11a-hexahydro[1,3]oxazolo[3,2-a]pyrido[1,2-d]pryrazine-8-carboxamide(compound 1a of Scheme 2) and a prodrug, Example 12.

DETAILED DESCRIPTION OF THE INVENTION

The present invention includes the compounds of Formula (I), useful indelivering therapeutic agents for treating or preventing viralinfections, particularly HIV infections, pharmaceutical compositionscomprising compounds of Formula (I), and processes for preparing thecompounds.

The present invention features a compound of formula (I):

wherein:R¹ is C₁-C₈alkyl, C₆-C₁₀aryl or LR²;L is alkylene;R² isa) hydroxy;b) alkoxy;c) OR³ wherein R³ is P(O)(OH)₂, alkoxy, or alkylene-alkoxy;d) heterocyclyl optionally substituted with oxo or C₁-C₈alkyl;e) C(O)OR⁴ wherein R⁴ is H, C₁-C₈alkyl, or XR⁵ wherein X is alkylene andR⁵ is C₆-C₁₀aryl, heterocyclyl, or NR⁶R⁷ wherein R⁶ and R⁷ areindependently selected from the group consisting of H and C₁-C₈alkyl;f) NR⁶R⁷;g) C(O)NR⁸R⁹ wherein R⁸ and R⁹ are independently selected from the groupconsisting of H and XR⁵; orh) C(O)R¹⁰ wherein R¹⁰ is heterocyclyl optionally substituted with XR¹¹wherein R¹¹ is heterocyclyl;or a pharmaceutically acceptable salt thereof.

The present invention features a compound of formula (I) wherein R¹ isLR² wherein R² is OR³ or C(O)OR⁴.

The present invention features a compound of formula (I) wherein R¹ isLR² wherein R² is OR³ or C(O)OR⁴ wherein R³ is P(O)(OH)₂ and R⁴ is XR⁵wherein X is alkylene and R⁵ is C₆₋₁₀aryl.

The present invention also features a compound selected from the groupconsisting of:

-   {[(3S,11aR)-8-({[(2,4-Difluorophenyl)methyl]amino}carbonyl)-3-methyl-5,7-dioxo-2,3,5,7,11,11a-hexahydro[1,3]oxazolo[3,2-a]pyrido[1,2-d]pyrazin-6-yl]oxy}methyl    methyl carbonate;-   {[(3S,11aR)-8-({[(2,4-Difluorophenyl)methyl]amino}carbonyl)-3-methyl-5,7-dioxo-2,3,5,7,11,11a-hexahydro[1,3]oxazolo[3,2-a]pyrido[1,2-d]pyrazin-6-yl]oxy}methyl    2-(methyloxy)ethyl carbonate;-   {[(3S,11aR)-8-({[(2,4-Difluorophenyl)methyl]amino}carbonyl)-3-methyl-5,7-dioxo-2,3,5,7,11,11a-hexahydro[1,3]oxazolo[3,2-a]pyrido[1,2-d]pyrazin-6-yl]oxy}methyl    1-methylethyl carbonate;-   {[(3S,11aR)-8-({[(2,4-Difluorophenyl)methyl]amino}carbonyl)-3-methyl-5,7-dioxo-2,3,5,7,11,11a-hexahydro[1,3]oxazolo[3,2-a]pyrido[1,2-d]pyrazin-6-yl]oxy}methyl    2-{[2-(methyloxy)ethyl]oxy}ethyl carbonate;-   {[(3S,11aR)-8-({[(2,4-Difluorophenyl)methyl]amino}carbonyl)-3-methyl-5,7-dioxo-2,3,5,7,11,11a-hexahydro[1,3]oxazolo[3,2-a]pyrido[1,2-d]pyrazin-6-yl]oxy}methyl    2-hydroxyethyl carbonate;-   {[(3S,11aR)-8-({[(2,4-Difluorophenyl)methyl]amino}carbonyl)-3-methyl-5,7-dioxo-2,3,5,7,11,11a-hexahydro[1,3]oxazolo[3,2-a]pyrido[1,2-d]pyrazin-6-yl]oxy}methyl    2-(phosphonooxy)ethyl carbonate;-   {[(3S,11aR)-8-({[(2,4-Difluorophenyl)methyl]amino}carbonyl)-3-methyl-5,7-dioxo-2,3,5,7,11,11a-hexahydro[1,3]oxazolo[3,2-a]pyrido[1,2-d]pyrazin-6-yl]oxy}methyl    3-hydroxypropyl carbonate;-   {[(3S,11aR)-8-({[(2,4-Difluorophenyl)methyl]amino}carbonyl)-3-methyl-5,7-dioxo-2,3,5,7,11,11a-hexahydro[1,3]oxazolo[3,2-a]pyrido[1,2-d]pyrazin-6-yl]oxy}methyl    3-(phosphonooxy)propyl carbonate;-   {[(3S,11aR)-8-({[(2,4-Difluorophenyl)methyl]amino}carbonyl)-3-methyl-5,7-dioxo-2,3,5,7,11,11a-hexahydro[1,3]oxazolo[3,2-a]pyrido[1,2-d]pyrazin-6-yl]oxy}methyl    2-pyridinylmethyl carbonate;-   {[(3S,11aR)-8-({[(2,4-Difluorophenyl)methyl]amino}carbonyl)-3-methyl-5,7-dioxo-2,3,5,7,11,11a-hexahydro[1,3]oxazolo[3,2-a]pyrido[1,2-d]pyrazin-6-yl]oxy}methyl    2-(2-oxo-1-pyrrolidinyl)ethyl carbonate;-   {[(3S,11aR)-8-({[(2,4-Difluorophenyl)methyl]amino}carbonyl)-3-methyl-5,7-dioxo-2,3,5,7,11,11a-hexahydro[1,3]oxazolo[3,2-a]pyrido[1,2-d]pyrazin-6-yl]oxy}methyl    2-(4-morpholinyl)ethyl carbonate;-   Phenylmethyl    ({[({[(3S,11aR)-8-({[(2,4-difluorophenyl)methyl]amino}carbonyl)-3-methyl-5,7-dioxo-2,3,5,7,11,11a-hexahydro[1,3]oxazolo[3,2-a]pyrido[1,2-d]pyrazin-6-yl]oxy}methyl)oxy]carbonyl}oxy)acetate;-   ({[({[(3S,11aR)-8-({[(2,4-Difluorophenyl)methyl]amino}carbonyl)-3-methyl-5,7-dioxo-2,3,5,7,11,11a-hexahydro[1,3]oxazolo[3,2-a]pyrido[1,2-d]pyrazin-6-yl]oxy}methyl)oxy]carbonyl}oxy)acetic    acid;-   {[(3S,11aR)-8-({[(2,4-Difluorophenyl)methyl]amino}carbonyl)-3-methyl-5,7-dioxo-2,3,5,7,11,11a-hexahydro[1,3]oxazolo[3,2-a]pyrido[1,2-d]pyrazin-6-yl]oxy}methyl    2-(dimethylamino)ethyl carbonate;-   {[(3S,11aR)-8-({[(2,4-Difluorophenyl)methyl]amino}carbonyl)-3-methyl-5,7-dioxo-2,3,5,7,11,11a-hexahydro[1,3]oxazolo[3,2-a]pyrido[1,2-d]pyrazin-6-yl]oxy}methyl    2-oxo-2-{4-[2-(1-pyrrolidinyl)ethyl]-1-piperazinyl}ethyl carbonate;-   Methyl    ({[({[(3S,11aR)-8-({[(2,4-difluorophenyl)methyl]amino}carbonyl)-3-methyl-5,7-dioxo-2,3,5,7,11,11a-hexahydro[1,3]oxazolo[3,2-a]pyrido[1,2-d]pyrazin-6-yl]oxy}methyl)oxy]carbonyl}oxy)acetate;-   {[(3S,11aR)-8-({[(2,4-Difluorophenyl)methyl]amino}carbonyl)-3-methyl-5,7-dioxo-2,3,5,7,11,11a-hexahydro[1,3]oxazolo[3,2-a]pyrido[1,2-d]pyrazin-6-yl]oxy}methyl    2-oxo-2-[(2-pyridinylmethyl)amino]ethyl carbonate;-   {[(3S,11aR)-8-({[(2,4-Difluorophenyl)methyl]amino}carbonyl)-3-methyl-5,7-dioxo-2,3,5,7,11,11a-hexahydro[1,3]oxazolo[3,2-a]pyrido[1,2-d]pyrazin-6-yl]oxy}methyl    2-(4-methyl-1-piperazinyl)ethyl carbonate;-   {[(3S,11aR)-8-({[(2,4-Difluorophenyl)methyl]amino}carbonyl)-3-methyl-5,7-dioxo-2,3,5,7,11,11a-hexahydro[1,3]oxazolo[3,2-a]pyrido[1,2-d]pyrazin-6-yl]oxy}methyl    2-{[2-(4-morpholinyl)ethyl]amino}-2-oxoethyl carbonate;-   {[(3S,11aR)-8-({[(2,4-Difluorophenyl)methyl]amino}carbonyl)-3-methyl-5,7-dioxo-2,3,5,7,11,11a-hexahydro[1,3]oxazolo[3,2-a]pyrido[1,2-d]pyrazin-6-yl]oxy}methyl    2-{[4-(dimethylamino)butyl]amino}-2-oxoethyl carbonate;-   {[(3S,11aR)-8-({[(2,4-Difluorophenyl)methyl]amino}carbonyl)-3-methyl-5,7-dioxo-2,3,5,7,11,11a-hexahydro[1,3]oxazolo[3,2-a]pyrido[1,2-d]pyrazin-6-yl]oxy}methyl    2-{[3-(1H-imidazol-1-yl)propyl]amino}-2-oxoethyl carbonate;-   2-Pyridinylmethyl    ({[({[(3S,11aR)-8-({[(2,4-difluorophenyl)methyl]amino}carbonyl)-3-methyl-5,7-dioxo-2,3,5,7,11,11a-hexahydro[1,3]oxazolo[3,2-a]pyrido[1,2-d]pyrazin-6-yl]oxy}methyl)oxy]carbonyl}oxy)acetate;-   2-(4-Morpholinyl)ethyl    ({[({[(3S,11aR)-8-({[(2,4-difluorophenyl)methyl]amino}carbonyl)-3-methyl-5,7-dioxo-2,3,5,7,11,11a-hexahydro[1,3]oxazolo[3,2-a]pyrido[1,2-d]pyrazin-6-yl]oxy}methyl)oxy]carbonyl}oxy)acetate;-   2-(Dimethylamino)ethyl    ({[({[(3S,11aR)-8-({[(2,4-difluorophenyl)methyl]amino}carbonyl)-3-methyl-5,7-dioxo-2,3,5,7,11,11a-hexahydro[1,3]oxazolo[3,2-a]pyrido[1,2-d]pyrazin-6-yl]oxy}methyl)oxy]carbonyl}oxy)acetate;-   {[(3S,11aR)-8-({[(2,4-Difluorophenyl)methyl]amino}carbonyl)-3-methyl-5,7-dioxo-2,3,5,7,11,11a-hexahydro[1,3]oxazolo[3,2-a]pyrido[1,2-d]pyrazin-6-yl]oxy}methyl    4-nitrophenyl carbonate; and-   pharmaceutically acceptable salts thereof.

The present invention also features a compound selected from the groupconsisting of: A compound selected from the group consisting of:

-   {[(3S,11aR)-8-({[(2,4-Difluorophenyl)methyl]amino}carbonyl)-3-methyl-5,7-dioxo-2,3,5,7,11,11a-hexahydro[1,3]oxazolo[3,2-a]pyrido[1,2-d]pyrazin-6-yl]oxy}methyl    2-(phosphonooxy)ethyl carbonate mono-sodium salt;-   {[(3S,11aR)-8-({[(2,4-Difluorophenyl)methyl]amino}carbonyl)-3-methyl-5,7-dioxo-2,3,5,7,11,11a-hexahydro[1,3]oxazolo[3,2-a]pyrido[1,2-d]pyrazin-6-yl]oxy}methyl    3-(phosphonooxy)propyl carbonate mono-sodium salt; and-   {[(3S,11aR)-8-({[(2,4-Difluorophenyl)methyl]amino}carbonyl)-3-methyl-5,7-dioxo-2,3,5,7,11,11a-hexahydro[1,3]oxazolo[3,2-a]pyrido[1,2-d]pyrazin-6-yl]oxy}methyl    2-(4-morpholinyl)ethyl carbonate acetate.

The term “alkyl”, alone or in combination with any other term, refers toa straight-chain or branched-chain saturated aliphatic hydrocarbonradical containing the specified number of carbon atoms. Examples ofalkyl radicals include, but are not limited to, methyl, ethyl, n-propyl,isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isoamyl,n-hexyl and the like.

The term “alkylene” refers to a straight or branched chain divalenthydrocarbon radical, preferably having from one to twelve carbon atoms,unless otherwise defined. Examples of “alkylene” as used herein include,but are not limited to, methylene, ethylene, propylene, butylene,isobutylene and the like.

The term “alkoxy” refers to an alkyl ether radical, wherein the term“alkyl” is defined above. Examples of suitable alkyl ether radicalsinclude, but are not limited to, methoxy, ethoxy, n-propoxy, isopropoxy,n-butoxy, isobutoxy, sec-butoxy, tert-butoxy and the like.

The term “aryl” alone or in combination with any other term, refers to acarbocyclic aromatic moiety (such as phenyl or naphthyl) containing thespecified number of carbon atoms, preferably from 6-10 carbon atoms.Examples of aryl radicals include, but are not limited to, phenyl,naphthyl, indenyl, azulenyl, fluorenyl, anthracenyl, phenanthrenyl,tetrahydronaphthyl, indanyl, phenanthridinyl and the like. Unlessotherwise indicated, the term “aryl” also includes each possiblepositional isomer of an aromatic hydrocarbon radical, such as in1-naphthyl, 2-naphthyl, 5-tetrahydronaphthyl, 6-tetrahydronaphthyl,1-phenanthridinyl, 2-phenanthridinyl, 3-phenanthridinyl,4-phenanthridinyl, 7-phenanthridinyl, 8-phenanthridinyl,9-phenanthridinyl and 10-phenanthridinyl. Examples of aryl radicalsinclude, but are not limited to, phenyl, naphthyl, indenyl, azulenyl,fluorenyl, anthracenyl, phenanthrenyl, tetrahydronaphthyl, indanyl,phenanthridinyl and the like.

The term “heterocycle,” “heterocyclic,” and “heterocyclyl” as usedherein, refer to a 3- to 7-membered monocyclic heterocyclic ring or 8-to 11-membered bicyclic heterocyclic ring system any ring of which iseither saturated, partially saturated or unsaturated, and which may beoptionally benzofused if monocyclic. Each heterocycle consists of one ormore carbon atoms and from one to four heteroatoms selected from thegroup consisting of N, O and S, and wherein the nitrogen and sulfurheteroatoms may optionally be oxidized, and the nitrogen atom mayoptionally be quaternized, and including any bicyclic group in which anyof the above-defined heterocyclic rings is fused to a benzene ring. Theheterocyclic ring may be attached at any carbon or heteroatom, providedthat the attachment results in the creation of a stable structure.Preferred heterocycles include 5-7 membered monocyclic heterocycles and8-10 membered bicyclic heterocycles. When the heterocyclic ring hassubstituents, it is understood that the substituents may be attached toany atom in the ring, whether a heteroatom or a carbon atom, providedthat a stable chemical structure results. “Heteroaromatics” or“heteroaryl” are included within the heterocycles as defined above andgenerally refers to a heterocycle in which the ring system is anaromatic monocyclic or polycyclic ring radical containing five to twentycarbon atoms, preferably five to ten carbon atoms, in which one or morering carbons, preferably one to four, are each replaced by a heteroatomsuch as N, O, S and P. Preferred heteroaryl groups include 5-6 memberedmonocyclic heteroaryls and 8-10 membered bicyclic heteroaryls. Alsoincluded within the scope of the term “heterocycle, “heterocyclic” or“heterocyclyl” is a group in which a non-aromatic heteroatom-containingring is fused to one or more aromatic rings, such as in an indolinyl,chromanyl, phenanthridinyl or tetrahydro-quinolinyl, where the radicalor point of attachment is on the non-aromatic heteroatom-containingring. Unless otherwise indicated, the term “heterocycle, “heterocyclic”or “heterocyclyl” also included each possible positional isomer of aheterocyclic radical, such as in 1-indolinyl, 2-indolinyl, 3-indolinyl.Examples of heterocycles include imidazolyl, imidazolinoyl,imidazolidinyl, quinolyl, isoquinolyl, indolyl, indazolyl,indazolinolyl, perhydropyridazyl, pyridazyl, pyridyl, pyrrolyl,pyrrolinyl, pyrrolidinyl, pyrazolyl, pyrazinyl, quinoxolyl, piperidinyl,pyranyl, pyrazolinyl, piperazinyl, pyrimidinyl, pyridazinyl,morpholinyl, thiamorpholinyl, furyl, thienyl, triazolyl, thiazolyl,carbolinyl, tetrazolyl, thiazolidinyl, benzofuranoyl, thiamorpholinylsulfone, oxazolyl, oxadiazolyl, benzoxazolyl, oxopiperidinyl,oxopyrrolidinyl, oxoazepinyl, azepinyl, isoxozolyl, isothiazolyl,furazanyl, tetrahydropyranyl, tetrahydrofuranyl, thiazolyl, thiadiazoyl,dioxolyl, dioxinyl, oxathiolyl, benzodioxolyl, dithiolyl, thiophenyl,tetrahydrothiophenyl, sulfolanyl, dioxanyl, dioxolanyl,tetahydrofurodihydrofuranyl, tetrahydropyranodihydrofuranyl,dihydropyranyl, tetradyrofurofuranyl and tetrahydropyranofuranyl.

The term “heteroatom” means nitrogen, oxygen, or sulfur and includes anyoxidized form of nitrogen, such as N(O) {N⁺—O⁻} and sulfur such as S(O)and S(O)₂, and the quaternized form of any basic nitrogen.

A combination of substituents or variables is permissible only if such acombination results in a stable or chemically feasible compound.

Unless otherwise stated, structures depicted herein are also meant toinclude all stereochemical forms of the structure, i.e., the R and Sconfigurations for each asymmetric center. Therefore, racemates andracemic mixtures, single enantiomers, diastereomeric mixtures andindividual diastereoisomers of the present compounds are expresslyincluded within the scope of the invention. Although the specificcompounds exemplified herein may be depicted in a particularstereochemical configuration, compounds having either the oppositestereochemistry at any given chiral center or mixtures thereof are alsoenvisioned.

Unless otherwise stated, structures depicted herein are also meant toinclude compounds which differ only in the presence of one or moreisotopically enriched atoms. For example, compounds having the presentstructures except for the replacement of a hydrogen by a deuterium ortritium, or the replacement of a carbon by a ¹³C- or ¹⁴C-enriched carbonare also within the scope of this invention.

It will be apparent to one skilled in the art that certain compounds ofthis invention may exist in alternative tautomeric forms. All suchtautomeric forms of the present compounds are within the scope of theinvention. Unless otherwise indicated, the representation of eithertautomer is meant to include the other.

The term “pharmaceutically effective amount” refers to an amounteffective in treating a virus infection, for example an HIV infection,in a patient either as monotherapy or in combination with other agents.The term “treating” as used herein refers to the alleviation of symptomsof a particular disorder in a patient, or the improvement of anascertainable measurement associated with a particular disorder, and mayinclude the suppression of symptom recurrence in an asymptomatic patientsuch as a patient in whom a viral infection has become latent. The term“prophylactically effective amount” refers to an amount effective inpreventing a virus infection, for example an HIV infection, orpreventing the occurrence of symptoms of such an infection, in apatient. As used herein, the term “patient” refers to a mammal,including a human.

The term “pharmaceutically acceptable carrier or adjuvant” refers to acarrier or adjuvant that may be administered to a patient, together witha compound of this invention, and which does not destroy thepharmacological activity thereof and is nontoxic when administered indoses sufficient to deliver a therapeutic amount of the antiviral agent.

The term “treatment” as used herein refers to the alleviation ofsymptoms of a particular disorder in a patient, or the improvement of anascertainable measurement associated with a particular disorder, and mayinclude the suppression of symptom recurrence in an asymptomatic patientsuch as a patient in whom a viral infection has become latent. Treatmentincludes prophylaxis which refers to preventing a disease or conditionor preventing the occurrence of symptoms of such a disease or condition,in a patient. As used herein, the term “patient” refers to a mammal,including a human.

As used herein, the term “subject” refers to a patient, animal or abiological sample. The term “biological sample”, as used herein,includes, without limitation, cell cultures or extracts thereof;preparations of an enzyme suitable for in vitro assay; biopsied materialobtained from a mammal or extracts thereof; and blood, saliva, urine,feces, semen, tears, or other body fluids or extracts thereof.

Pharmaceutically acceptable salts of the compounds according to theinvention include those derived from pharmaceutically acceptableinorganic and organic acids and bases. Examples of suitable acidsinclude hydrochloric, hydrobromic, sulfuric, nitric, perchloric,fumaric, maleic, phosphoric, glycollic, lactic, salicyclic, succinic,toluene-p-sulfonic, tartaric, acetic, citric, methanesulfonic,ethanesulfonic, formic, benzoic, malonic, naphthalene-2-sulfonic andbenzenesulfonic acids. Other acids, such as oxalic, while not inthemselves pharmaceutically acceptable, may be employed in thepreparation of salts useful as intermediates in obtaining the compoundsof the invention and their pharmaceutically acceptable acid additionsalts.

Salts derived from appropriate bases include alkali metal (e.g. sodium),alkaline earth metal (e.g., magnesium), ammonium, NW₄ ⁺ (wherein W isC₁₋₄ alkyl) and other amine salts. Physiologically acceptable salts of ahydrogen atom or an amino group include salts or organic carboxylicacids such as acetic, lactic, tartaric, malic, isethionic, lactobionicand succinic acids; organic sulfonic acids such as methanesulfonic,ethanesulfonic, benzenesulfonic and p-toluenesulfonic acids andinorganic acids such as hydrochloric, sulfuric, phosphoric and sulfamicacids. Physiologically acceptable salts of a compound with a hydroxygroup include the anion of said compound in combination with a suitablecation such as Na⁺, NH₄ ⁺, and NW₄ ⁺ (wherein W is a C₁₋₄alkyl group).Preferred salts include sodium, calcium, potassium, and hydrochloride.

Other compounds of this invention may be prepared by one skilled in theart following the teachings of the specification coupled with knowledgein the art using reagents that are readily synthesized or commerciallyavailable.

Any reference to any of the above compounds also includes a reference toa pharmaceutically acceptable salt thereof.

Salts of the compounds of the present invention may be made by methodsknown to a person skilled in the art. For example, treatment of acompound of the present invention with an appropriate base or acid in anappropriate solvent will yield the corresponding salt.

Compounds of the present invention are useful as prodrugs to delivertherapeutic compounds, for examples compounds disclosed inWO2006/116764, which were demonstrated to have HIV integrase inhibitoryactivity. One aspect of the instant invention relates to methods oftreating or preventing viral infection, for example an HIV infection, ina biological sample comprising contacting the biological sample withcompounds of formula (I) or pharmaceutically acceptable salts thereof.Another aspect of the instant invention relates to methods of treatingor preventing viral infection, for example, an HIV infection, in a humancomprising administering to the human a therapeutically effective amountof compounds of formula (I) or pharmaceutically acceptable saltsthereof.

The compounds according to the invention are particularly suited to thetreatment or prophylaxis of HIV infections and associated conditions.Reference herein to treatment extends to prophylaxis as well as thetreatment of established infections, symptoms, and associated clinicalconditions such as AIDS related complex (ARC), Kaposi's sarcoma, andAIDS dementia.

According to one embodiment of the invention, compounds of formula (I)or salts thereof may be formulated into compositions. In a preferredembodiment, the composition is a pharmaceutical composition, whichcomprises a compound of formula (I) and pharmaceutically acceptablecarrier, adjuvant or vehicle. In one embodiment, the compositioncomprises an amount of a compound of the present invention effective totreat or prevent viral infection, for example an HIV infection, in abiological sample or in a patient. In another embodiment, compounds ofthis invention and pharmaceutical compositions thereof, which comprisean amount of a compound of the present innovation effective to inhibitviral replication or to treat or prevent a viral infection or disease ordisorder, for example an HIV infection, and a pharmaceuticallyacceptable carrier, adjuvant or vehicle, may be formulated foradministration to a patient, for example, for oral administration.

The present invention features compounds according to the invention foruse in medical therapy, for example for the treatment or prophylaxis ofa viral infection, for example an HIV infection and associatedconditions. The compounds according to the invention are especiallyuseful for the treatment of AIDS and related clinical conditions such asAIDS related complex (ARC), progressive generalized lymphadenopathy(PGL), Kaposi's sarcoma, thromobocytopenic purpura, AIDS-relatedneurological conditions such as AIDS dementia complex, multiplesclerosis or tropical paraperesis, anti-HIV antibody-positive andHIV-positive conditions, including such conditions in asymptomaticpatients.

According to another aspect, the present invention provides a method forthe treatment or prevention of the symptoms or effects of a viralinfection in an infected patient, for example, a mammal including ahuman, which comprises administering to said patient a pharmaceuticallyeffective amount of a compound according to the invention. According toone aspect of the invention, the viral infection is a retroviralinfection, in particular an HIV infection.

The present invention further includes the use of a compound accordingto the invention in the manufacture of a medicament for administrationto a subject for the treatment of a viral infection, in particular andHIV infection.

The compounds according to the invention may also be used in adjuvanttherapy in the treatment of HIV infections or HIV-associated symptoms oreffects, for example Kaposi's sarcoma.

The present invention further provides a method for the treatment of aclinical condition in a patient, for example, a mammal including a humanwhich clinical condition includes those which have been discussedhereinbefore, which comprises treating said patient with apharmaceutically effective amount of a compound according to theinvention. The present invention also includes a method for thetreatment or prophylaxis of any of the aforementioned diseases orconditions.

Reference herein to treatment extends to prophylaxis as well as thetreatment of established conditions, disorders and infections, symptomsthereof, and associated. The above compounds according to the inventionand their pharmaceutically acceptable salts may be employed incombination with other therapeutic agents for the treatment of the aboveinfections or conditions. Combination therapies according to the presentinvention comprise the administration of a compound of the presentinvention or a pharmaceutically acceptable salt thereof and anotherpharmaceutically active agent. The active ingredient(s) andpharmaceutically active agents may be administered simultaneously (i.e.,concurrently) in either the same or different pharmaceuticalcompositions or sequentially in any order. The amounts of the activeingredient(s) and pharmaceutically active agent(s) and the relativetimings of administration will be selected in order to achieve thedesired combined therapeutic effect.

Examples of other therapeutic agents include:

Nucleotide reverse transcriptase inhibitors such as zidovudine,didanosine, lamivudine, zalcitabine, abacavir, stavidine, adefovir,adefovir dipivoxil, fozivudine, todoxil, emtricitabine, alovudine,amdoxovir, elvucitabine, and similar agents;

Non-nucleotide reverse transcriptase inhibitors (including an agenthaving anti-oxidation activity such as immunocal, oltipraz, etc.) suchas nevirapine, delavirdine, efavirenz, loviride, immunocal, oltipraz,capravirine, TMC-278, TMC-125, etravirine, and similar agents;

Protease inhibitors such as saquinavir, ritonavir, indinavir,nelfinavir, amprenavir, fosamprenavir, brecanavir, atazanavir,tipranavir, palinavir, lasinavir, and similar agents;

Entry inhibitors such as enfuvirtide (T-20), T-1249, PRO-542, PRO-140,TNX-355, BMS-806, 5-Helix and similar agents;

Integrase inhibitors such as L-870,810, raltegravir and similar agents;

Budding inhibitors such as PA-344 and PA-457, and similar agents; and

CXCR4 and/or CCR5 inhibitors such as vicriviroc (Sch-C), Sch-D, TAK779,maraviroc (UK 427,857), TAK449 and similar agents.

The present invention further includes the use of a compound accordingto the invention in the manufacture of a medicament for simultaneous orsequential administration with at least another therapeutic agent, suchas those defined hereinbefore.

Compounds of the present invention may be administered with an agentknown to inhibit or reduce the metabolism of compounds, for exampleritonavir. Accordingly, the present invention features a method for thetreatment or prophylaxis of a disease as hereinbefore described byadministration of a compound of the present invention in combinationwith a metabolic inhibitor. Such combination may be administeredsimultaneously or sequentially.

In general a suitable dose for each of the above-mentioned conditionswill be in the range of 0.01 to 250 mg per kilogram body weight of therecipient (e.g. a human) per day, preferably in the range of 0.1 to 100mg per kilogram body weight per day. Unless otherwise indicated, allweights of active ingredient are calculated as the parent compound offormula (I) for salts or esters thereof, the weights would be increasedproportionally. The desired dose may be presented as one, two, three,four, five, six or more sub-doses administered at appropriate intervalsthroughout the day. In some cases the desired dose may be given onalternative days. These sub-doses may be administered in unit dosageforms containing, for example, 1 to 1000 mg or 20 to 500 mg, or 10 to500 mg, or 1 to 400 mg of active ingredient per unit dosage form.

While it is possible for the active ingredient to be administered alone,it is preferable to present it as a pharmaceutical composition. Thecompositions of the present invention comprise at least one activeingredient, as defined above, together with one or more acceptablecarriers thereof and optionally other therapeutic agents. Each carriermust be acceptable in the sense of being compatible with the otheringredients of the composition and not injurious to the patient.

Pharmaceutical compositions include those suitable for oral, rectal,nasal, topical (including transdermal, buccal and sublingual), vaginalor parenteral (including subcutaneous, intramuscular, intravenous,intradermal, and intravitreal) administration. The compositions mayconveniently be presented in unit dosage form and may be prepared by anymethods well known in the art of pharmacy. Such methods represent afurther feature of the present invention and include the step ofbringing into association the active ingredients with the carrier, whichconstitutes one or more accessory ingredients. In general, thecompositions are prepared by uniformly and intimately bringing intoassociation the active ingredients with liquid carriers or finelydivided solid carriers or both, and then if necessary shaping theproduct.

The present invention further includes a pharmaceutical composition ashereinbefore defined wherein a compound of the present invention or apharmaceutically acceptable salt thereof and another therapeutic agentare presented separately from one another as a kit of parts.

Compositions suitable for transdermal administration may be presented asdiscrete patches adapted to remain in intimate contact with theepidermis of the recipient for a prolonged period of time. Such patchessuitably contain the active compound 1) in an optionally buffered,aqueous solution or 2) dissolved and/or dispersed in an adhesive or 3)dispersed in a polymer. A suitable concentration of the active compoundis about 1% to 25%, preferably about 3% to 15%. As one particularpossibility, the active compound may be delivered from the patch byelectrotransport or iontophoresis as generally described inPharmaceutical Research 3(6), 318 (1986).

Pharmaceutical compositions of the present invention suitable for oraladministration may be presented as discrete units such as capsules,caplets, cachets or tablets each containing a predetermined amount ofthe active ingredients; as a powder or granules; as a solution or asuspension in an aqueous or non-aqueous liquid; or as an oil-in-waterliquid emulsion or a water-in-oil liquid emulsion. The active ingredientmay also be presented as a bolus, electuary or paste.

A tablet may be made by compression or molding, optionally with one ormore accessory ingredients. Compressed tablets may be prepared bycompressing in a suitable machine the active ingredients in afree-flowing form such as a powder or granules, optionally mixed with abinder (e.g. povidone, gelatin, hydroxypropylmethyl cellulose),lubricant, inert diluent, preservative, disintegrant (e.g. sodium starchglycollate, cross-linked povidone, cross-linked sodium carboxymethylcellulose) surface-active or dispersing agent. Molded tablets may bemade by molding a mixture of the powdered compound moistened with aninert liquid diluent in a suitable machine. The tablets may optionallybe coated or scored and may be formulated so as to provide slow orcontrolled release of the active ingredients therein using, for example,hydroxypropylmethyl cellulose in varying proportions to provide thedesired release profile. Tablets may optionally be provided with anenteric coating, to provide release in parts of the gut other than thestomach.

Pharmaceutical compositions suitable for topical administration in themouth include lozenges comprising the active ingredients in a flavoredbase, usually sucrose and acacia or tragacanth; pastilles comprising theactive ingredient in an inert basis such as gelatin and glycerin, orsucrose and acacia; and mouthwashes comprising the active ingredient ina suitable liquid carrier.

Pharmaceutical compositions suitable for vaginal administration may bepresented as pessaries, tampons, creams, gels, pastes, foams or spray.Pharmaceutical compositions may contain in addition to the activeingredient such carriers as are known in the art to be appropriate.

Pharmaceutical compositions for rectal administration may be presentedas a suppository with a suitable carrier comprising, for example, cocoabutter or a salicylate or other materials commonly used in the art. Thesuppositories may be conveniently formed by admixture of the activecombination with the softened or melted carrier(s) followed by chillingand shaping in molds.

Pharmaceutical compositions suitable for parenteral administrationinclude aqueous and nonaqueous isotonic sterile injection solutionswhich may contain anti-oxidants, buffers, bacteriostats and soluteswhich render the pharmaceutical composition isotonic with the blood ofthe intended recipient; and aqueous and non-aqueous sterile suspensionswhich may include suspending agents and thickening agents; and liposomesor other microparticulate systems which are designed to target thecompound to blood components or one or more organs. The pharmaceuticalcompositions may be presented in unit-dose or multi-dose sealedcontainers, for example, ampoules and vials, and may be stored in afreeze-dried (lyophilized) condition requiring only the addition of thesterile liquid carrier, for example water for injection, immediatelyprior to use. Extemporaneous injection solutions and suspensions may beprepared from sterile powders, granules and tablets of the kindpreviously described.

Unit dosage pharmaceutical compositions include those containing a dailydose or daily subdose of the active ingredients, as hereinbeforerecited, or an appropriate fraction thereof.

It should be understood that in addition to the ingredients particularlymentioned above the pharmaceutical compositions of this invention mayinclude other agents conventional in the art having regard to the typeof pharmaceutical composition in question, for example, those suitablefor oral administration may include such further agents as sweeteners,thickeners and flavoring agents.

The compounds of the present invention may be prepared according to thefollowing reactions schemes and examples, or modifications thereof usingreadily available starting materials, reagents and conventionalsynthesis procedures. In these reactions, it is also possible to makeuse of variants which are known to those of ordinary skill in the art.

(3S,11aR)—N-[(2,4-Difluorophenyl)methyl]-6-hydroxy-3-methyl-5,7-dioxo-2,3,5,7,11,11a-hexahydro[1,3]oxazolo[3,2-a]pyrido[1,2-d]pyrazine-8-carboxamidemay be made by methods know to those skilled in the art, includingmethods disclosed in WO2006/116724.

The following examples are intended for illustration only and are notintended to limit the scope of the invention in any way.

Preparation 1: (3S,11aR)—N-[(2,4-Difluorophenylmethyl]-6-hydroxy-3-methyl-5,7-dioxo-2,3,5,7,11,11a-hexahydro[1,3]oxazolo[3,2-a]pyrido[1,2-d]pyrazine-8-carboxamidesodium salt (compound 1b, scheme 2)

a) Synthesis of 2-methyl-3-[(phenylmethyl)oxy]-4H-pyran-4-one (compoundP-2). To a slurry of 2000 g of compound P-1 (1.0 eq.) in 14.0 L of MeCNwere added 2848 g of benzyl bromide (1.05 eq.) and 2630 g of K₂CO₃ (1.2eq.). The mixture was stirred at 80° C. for 5 h and cooled to 13° C.Precipitate was filtered and washed with 5.0 L of MeCN. The filtrate wasconcentrated and 3.0 L of THF was added to the residue. The THF solutionwas concentrated to give 3585 g of crude compound P-2 as oil. Withoutfurther purification, compound P-2 was used in the next step. ¹H NMR(300 MHz, CDCl₃) δ 7.60 (d, J=5.7 Hz, 1H), 7.4-7.3 (m, 5H), 6.37 (d,J=5.7 Hz, 1H), 5.17 (s, 2H), 2.09 (s, 3H).b) Synthesis of2-(2-hydroxy-2-phenylethyl)-3-[(phenylmethyl)oxy]-4H-pyran-4-one(compound P-3). To 904 g of the crude compound P-2 was added 5.88 L ofTHF and the solution was cooled to −60° C. 5.00 L of 1.0 M of Lithiumbis(trimethylsilylamide) in THF (1.25 eq.) was added dropwise for 2 h tothe solution of compound 2 at −60° C. Then, a solution of 509 g ofbenzaldehyde (1.2 eq.) in 800 mL of THF was added at −60° C. and thereaction mixture was aged at −60° C. for 1 h. The THF solution waspoured into a mixture of 1.21 L of conc.HCl, 8.14 L of ice water and4.52 L of EtOAc at less than 2° C. The organic layer was washed with2.71 L of brine (twice) and the aqueous layer was extracted with 3.98 Lof EtOAc. The combined organic layers were concentrated. To the mixture,1.63 L of toluene was added and concentrated (twice) to provide tolueneslurry of compound P-3. Filtration, washing with 0.90 L of cold tolueneand drying afforded 955 g of compound P-3 (74% yield from compound P-1)as a solid. ¹H NMR (300 MHz, CDCl₃) δ 7.62 (d, J=5.7 Hz, 1H), 7.5-7.2(m, 10H), 6.38 (d, J=5.7 Hz, 1H), 5.16 (d, J=11.4 Hz, 1H), 5.09 (d,J=11.4 Hz, 1H), 4.95 (dd, J=4.8, 9.0 Hz, 1H), 3.01 (dd, J=9.0, 14.1 Hz,1H), 2.84 (dd, J=4.8, 14.1 Hz, 1H).c) Synthesis of2-[(E)-2-phenylethenyl]-3-[(phenylmethyl)oxy]-4H-pyran-4-one (compoundP-4). To a solution of 882 g of compound P-3 (1.0 eq.) in 8.82 L of THFwere added 416 g of Et₃N (1.5 eq.) and 408 g of methanesulfonyl chloride(1.3 eq.) at less than 30° C. After confirmation of disappearance ofcompound P-3, 440 mL of NMP and 1167 g of DBU (2.8 eq.) were added tothe reaction mixture at less than 30° C. and the reaction mixture wasaged for 30 min. The mixture was neutralized with 1.76 L of 16% sulfuricacid and the organic layer was washed with 1.76 L of 2% Na₂SO₃aq. Afterconcentration of the organic layer, 4.41 L of toluene was added and themixture was concentrated (tree times). After addition of 4.67 L ofhexane, the mixture was cooled with ice bath. Filtration, washing with1.77 L of hexane and drying provided 780 g of compound P-4 (94% yield)as a solid. ¹H NMR (300 MHz, CDCl₃) δ 7.69 (d, J=5.7 Hz, 1H), 7.50-7.25(m, 10H), 7.22 (d, J=16.2 Hz, 1H), 7.03 (d, J=16.2 Hz, 1H), 6.41 (d,J=5.7 Hz, 1H), 5.27 (s, 2H).d) Synthesis of 4-oxo-3-[(phenylmethyl)oxy]-4H-pyran-2-carboxylic acid(compound P-5). To a mixture of 822 g of compound P-4 (1.0 eq.) and 11.2g of RuCl₃.nH₂O (0.02 eq.) in 2.47 L of MeCN, 2.47 L of EtOAc and 2.47 Lof H₂O was added 2310 g of NaIO₄ (4.0 eq.) at less than 25° C. Afteraging for 1 h, 733 g of NaClO₂ (3.0 eq.) was added to the mixture atless than 25° C. After aging for 1 h, precipitate was filtered andwashed with 8.22 L of EtOAc. To the filtrate, 1.64 L of 50% Na₂S₂O₃aq,822 mL of H₂O and 630 mL of coc.HCl were added. The aqueous layer wasextracted with 4.11 L of EtOAc and the organic layers were combined andconcentrated. To the residue, 4 L of toluene was added and the mixturewas concentrated and cooled with ice bath. Filtration, washing with 1 Lof toluene and drying provided 372 g of compound P-5 (56% yield) as asolid. ¹H NMR (300 MHz, CDCl₃) δ 7.78 (d, J=5.7 Hz, 1H), 7.54-7.46 (m,2H), 7.40-7.26 (m, 3H), 6.48 (d, J=5.7 Hz, 1H), 5.6 (brs, 1H), 5.31 (s,2H).e) Synthesis of1-(2,3-dihydroxypropyl)-4-oxo-3-[(phenylmethyl)oxy]-1,4-dihydro-2-pyridinecarboxylicacid (compound P-6). A mixture of 509 g of compound P-5 (1.0 eq.) and407 g of 3-amino-propane-1,2-diol (2.5 eq.) in 1.53 L of EtOH wasstirred at 65° C. for 1 h and at 80° C. for 6 h. After addition of 18.8g of 3-Amino-propane-1,2-diol (0.1 eq.) in 200 mL of EtOH, the mixturewas stirred at 80° C. for 1 h. After addition of 18.8 g of3-amino-propane-1,2-diol (0.1 eq.) in 200 mL of EtOH, the mixture wasstirred at 80° C. for 30 min. After cooling and addition of 509 mL ofH₂O, the mixture was concentrated. To the residue, 2.54 L of H₂O and2.54 L of AcOEt were added. After separation, the aqueous layer waswashed with 1.02 L of EtOAc. To the aqueous layer, 2.03 L of 12%sulfuric acid was added at less than 12° C. to give crystal of compoundP-6. Filtration, washing with 1.53 L of cold H₂O and drying provided 576g of compound P-6 (83% yield) as a solid. ¹H NMR (300 MHz, DMSO-d₆) δ7.67 (d, J=7.5 Hz, 1H), 7.5-7.2 (m, 5H), 6.40 (d, J=7.5 Hz, 1H), 5.07(s, 2H), 4.2-4.0 (m, 1H), 3.9-3.6 (m, 2H), 3.38 (dd, J=4.2, 10.8 Hz,1H), 3.27 (dd, J=6.0, 10.8 Hz, 1H).f) Synthesis of methyl1-(2,3-dihydroxypropyl)-4-oxo-3-[(phenylmethyl)oxy]-1,4-dihydro-2-pyridinecarboxylate(compound P-7). To a slurry of 576 g of compound P-6 (1.0 eq.: 5.8% ofH₂O was contained) in 2.88 L of NMP were added 431 g of NaHCO₃ (3.0 eq.)and 160 mL of methyl iodide (1.5 eq.) and the mixture was stirred atroom temperature for 4 h. After cooling to 5° C., 1.71 L of 2N HCl and1.15 L of 20% NaClaq were added to the mixture at less than 10° C. togive crystal of compound 7. Filtration, washing with 1.73 L of H₂O anddrying provided 507 g of compound P-7 (89% yield) as a solid. ¹H NMR(300 MHz, DMSO-d₆) δ 7.59 (d, J=7.5 Hz, 1H), 7.40-7.28 (m, 5H), 6.28 (d,J=7.5 Hz, 1H), 5.21 (d, J=5.4 Hz, 1H), 5.12 (d, J=10.8 Hz, 1H), 5.07 (d,J=10.8 Hz, 1H), 4.83 (t, J=5.7 Hz, 1H), 3.97 (dd, J=2.4, 14.1 Hz, 1H),3.79 (s, 3H), 3.70 (dd, J=9.0, 14.4 Hz, 1H), 3.65-3.50 (m, 1H),3.40-3.28 (m, 1H), 3.26-3.14 (m, 1H).g) Synthesis of methyl1-(2,2-dihydroxyethyl)-4-oxo-3-[(phenylmethyl)oxy]-1,4-dihydro-2-pyridinecarboxylate(compound P-8). To a mixture of 507 g of compound P-7 (1.0 eq.) in 5.07L of MeCN, 5.07 L of H₂O and 9.13 g of AcOH (0.1 eq.) was added 390 g ofNaIO₄ (1.2 eq.) and the mixture was stirred at room temperature for 2 h.After addition of 1.52 L of 10% Na₂S₂O₃aq., the mixture was concentratedand cooled to 10° C. Filtration, washing with H₂O and drying provided386 g of compound P-8 (80% yield) as a solid. ¹H NMR (300 MHz, DMSO-d₆)δ 7.62 (d, J=7.5 Hz, 1H), 7.42-7.30 (m, 5H), 6.33 (d, J=6.0 Hz, 2H),6.29 (d, J=7.5 Hz, 1H), 5.08 (s, 2H), 4.95-4.85 (m, 1H), 3.80 (s, 3H),3.74 (d, J=5.1 Hz, 2H).h) Synthesis of(3S,11aR)-3-methyl-6-[(phenylmethyl)oxy]-2,3,11,11a-tetrahydro[1,3]oxazolo[3,2-a]pyrido[1,2-d]pyrazine-5,7-dione(compound P-9). After dissolution of mixture of 320 g of compound P-8(1.0 eq.) in 3.20 L of MeOH by heating, the solution was concentrated.To the residue, 1.66 L of MeCN, 5.72 mL of AcOH (0.1 eq.) and 82.6 g of(S)-2-Amino-propan-1-ol (1.1 eq.) were added and the mixture was heatedto 70° C., stirred at 70° C. for 4 h and concentrated. To the residue,1.67 L of 2-propanol was added and the mixture was concentrated (twice).After cooling of the residue, filtration, washing with 500 mL of cold2-propanol and drying provided 167 g of compound P-9 (52% yield) as asolid. ¹H NMR (300 MHz, CDCl₃) δ 7.61-7.55 (m, 2H), 7.40-7.20 (m, 4H),6.53 (d, J=7.2, 1H), 5.46 (d, J=10.5 Hz, 1H), 5.23 (d, J=10.2 Hz, 1H),5.20 (dd, J=3.9, 9.6 Hz, 1H), 4.46-4.34 (m, 1H), 4.31 (dd, J=6.6, 8.7Hz, 1H), 4.14 (dd, J=3.9, 12.3 Hz, 1H), 3.79 (dd, J=9.9, 12.3 Hz, 1H),3.62 (dd, J=6.9, 8.7 Hz, 1H), 1.38 (d, J=6.3 Hz, 3H).i) Synthesis of(3S,11aR)-8-bromo-3-methyl-6-[(phenylmethyl)oxy]-2,3,11,11a-tetrahydro[1,3]oxazolo[3,2-a]pyrido[1,2-d]pyrazine-5,7-dione(compound P-10). To slurry of 156 g of compound P-9 (1.0 eq.) in 780 mLof NMP was added 93.6 g of NBS (1.1 eq.) and the mixture was stirred atroom temperature for 2.5 h. The reaction mixture was added to 3.12 L ofH₂O. Filtration, washing with 8.0 L of H₂O and drying provided 163 g ofcompound P-10 (84% yield) as a solid. ¹H NMR (300 MHz, DMSO-d₆) δ 8.37(s, 1H), 7.55-7.50 (m, 2H), 7.42-7.25 (m, 3H), 5.34 (dd, J=3.6, 9.9 Hz,1H), 5.18 (d, J=10.8 Hz, 1H), 5.03 (d, J=10.5 Hz, 1H), 4.53 (dd, J=3.6,12.0 Hz, 1H), 4.40-4.20 (m, 2H), 3.99 (dd, J=9.9, 11.7 Hz, 1H), 3.64(dd, J=5.7, 8.1 Hz, 1H), 1.27 (d, J=6.3 Hz, 3H).j) Synthesis of(3S,11aS)—N-[(2,4-difluorophenyl)methyl]-3-methyl-5,7-dioxo-6-[(phenylmethyl)oxy]-2,3,5,7,11,11a-hexahydro[1,3]oxazolo[3,2-a]pyrido[1,2-d]pyrazine-8-carboxamide(compound P-11). Under carbon mono-oxide atmosphere, a mixture of 163 gof compound P-10 (1.0 eq.), 163 mL of i-Pr₂NEt (2.5 eq.), 68.4 mL of2,4-difluorobenzylamine (1.5 eq.) and 22.5 g of Pd(PPh₃)₄ (0.05 eq.) in816 mL of DMSO was stirred at 90° C. for 7 h. After cooling, removal ofprecipitate, washing with 50 mL of DMSO and addition of 11.3 g ofPd(PPh₃)₄ (0.025 eq.), the reaction mixture was stirred at 90° C. for 2h under carbon mono-oxide atmosphere again. After cooling, removal ofprecipitate and addition of 2.0 L of AcOEt and 2.0 L of H₂O, the organiclayer was washed with 1.0 L of 1N HClaq. and 1.0 L of H₂O (twice) andthe aqueous layer was extracted with 1.0 L of AcOEt. The organic layerswere combined and concentrated. Silica gel column chromatography of theresidue provided 184 g of compound P-11 (96% yield) as foam. ¹H NMR (300MHz, CDCl₃) δ 10.38 (t, J=6.3 Hz, 1H), 8.39 (s, 1H), 7.75-7.25 (m, 7H),6.90-6.70 (m, 2H), 5.43 (d, J=10.2 Hz, 1H), 5.24 (d, J=10.2 Hz, 1H),5.19 (dd, J=3.9, 9.9 Hz, 1H), 4.63 (d, J=6.0 Hz, 2H), 4.50-4.25 (m, 3H),3.86 (dd, J=9.9, 12.3 Hz, 1H), 3.66 (dd, J=6.9, 8.4 Hz, 1H), 1.39 (d,J=6.0 Hz, 3H).k) Synthesis of(3S,11aR)—N-[(2,4-difluorophenyl)methyl]-6-hydroxy-3-methyl-5,7-dioxo-2,3,5,7,11,11a-hexahydro[1,3]oxazolo[3,2-a]pyrido[1,2-d]pyrazine-8-carboxamide(compound 1a). Under hydrogen atmosphere, a mixture of 184 g of compoundP-11 (1.0 eq.) and 36.8 g of 10% Pd—C in 3.31 L of THF and 0.37 L ofMeOH was stirred for 3 h. After filtration of precipitate (Pd—C),washing with THF/MeOH(9/1) and addition of 36.8 g of 10% Pd—C, themixture was stirred for 20 min under hydrogen atmosphere. Afterfiltration of precipitate (Pd—C) and washing with THF/MeOH(9/1), thefiltrate was concentrated. After 200 mL of AcOEt was added to theresidue, filtration afforded crude solid of compound 1a. Theprecipitates were combined and extracted with 4.0 L of CHCl₃/MeOH(5/1).After concentration of the CHCl₃/MeOH solution and addition of 250 mL ofAcOEt to the residue, filtration afforded crude solid of compound 1a.The crude solids were combined and dissolved in 8.2 L of MeCN/H₂O(9/1)by heating. After filtration, the filtrate was concentrated. To theresidue, 1.5 L of EtOH was added and the mixture was concentrated (threetimes). After cooling of the residue, filtration and drying provided 132g of compound 1a (88% yield) as a solid. ¹H NMR (300 MHz, DMSO-d₆) δ11.47 (brs, 1H), 10.31 (t, J=6.0 Hz, 1H), 8.46 (s, 1H), 7.40 (td, J=8.6,6.9 Hz, 1H), 7.24 (ddd, J=2.6, 9.4, 10.6, 1H), 7.11-7.01 (m, 1H), 5.39(dd, J=4.1, 10.4 Hz, 1H), 4.89 (dd, J=4.2, 12.3 Hz, 1H), 4.55 (d, J=6.0Hz, 2H), 4.40 (dd, J=6.8, 8.6 Hz, 1H), 4.36-4.22 (m, 1H), 4.00 (dd,J=10.2, 12.3 Hz, 1H), 3.67 (dd, J=6.7, 8.6 Hz, 1H), 1.34 (d, J=6.3 Hz,3H).l) Synthesis of(3S,11aR)—N-[(2,4-difluorophenyl)methyl]-6-hydroxy-3-methyl-5,7-dioxo-2,3,5,7,11,11a-hexahydro[1,3]oxazolo[3,2-a]pyrido[1,2-d]pyrazine-8-carboxamidesodium salt (compound 1b). After dissolution of 16.0 g of compound 1a(1.0 eq.) in 2.56 L of EtOH and 0.64 L of H₂O by heating, followed byfiltration, 39 mL of 1N NaOHaq. (1.0 eq.) was added to the solution at75° C. The solution was gradually cooled to room temperature.Filtration, washing with 80 mL of EtOH and drying provided 13.5 g ofcompound 1b (80% yield) as a solid. ¹H NMR (300 MHz, DMSO-d₆) δ 10.73(t, J=6.0 Hz, 1H), 7.89 (s, 1H), 7.40-7.30 (m, 1H), 7.25-7.16 (m, 1H),7.07-6.98 (m, 1H), 5.21 (dd, J=3.8, 10.0 Hz, 1H), 4.58 (dd, J=3.8, 12.1Hz, 1H), 4.51 (d, J=5.4 Hz, 2H), 4.30-4.20 (m, 2H), 3.75 (dd, J=10.0,12.1 Hz, 1H), 3.65-3.55 (m, 1H), 1.27 (d, J=6.1 Hz, 3H).

Example 1{[(3S,11aR)-8-({[(2,4-Difluorophenyl)methyl]amino}carbonyl)-3-methyl-5,7-dioxo-2,3,5,7,11,11a-hexahydro[1,3]oxazolo[3,2-a]pyrido[1,2-d]pyrazin-6-yl]oxy}methylmethyl carbonate

a) Chloromethyl methyl carbonate. Chloromethyl chloridocarbonate (3 ml,33.7 mmol) was dissolved in dichloromethane (10 mL) and cooled to 0° C.Methanol (1.36 mL, 33.7 mmol) was added dropwise, followed by pyridine(2.73 mL, 33.7 mmol) dropwise. The white suspension was stirred at 0° C.and allowed to warm to ambient temperature and stirred for 14 hours. Thesuspension was quenched with water, diluted with aqueous citric acid,extracted with dichloromethane, washed with sodium bicarbonate, brine,dried over sodium sulfate and concentrated under reduced pressure togive chloromethyl methyl carbonate as a clear colorless oil. ¹H NMR(CDCl₃) δ 5.72 (s, 2H), 3.96 (s, 3H).b) Iodomethyl methyl carbonate. Chloromethyl methyl carbonate (2.05 g,16.46 mmol) was dissolved in acetone and sodium iodide (3.70 g, 24.69mmol) was added and the reaction was heated at 40° C. for 15 hours. Theyellow suspension was allowed to cool to ambient temperature,concentrated under reduced pressure, diluted with water and aqueoussodium thiosulfate, extracted with dichloromethane, washed with brine,dried over sodium sulfate, and concentrated under reduced pressure togive iodomethyl methyl carbonate as a clear yellow oil. ¹H NMR (CDCl₃) δ5.92 (s, 2H), 3.93 (s, 3H).c){[(3S,11aR)-8-({[(2,4-Difluorophenyl)methyl]amino}carbonyl)-3-methyl-5,7-dioxo-2,3,5,7,11,11a-hexahydro[1,3]oxazolo[3,2-a]pyrido[1,2-d]pyrazin-6-yl]oxy}methylmethyl carbonate. 1b (30 mg, 0.070 mmol) and potassium carbonate (29 mg,0.209 mmol) were suspended in water and tetrabutylammonium hydrogensulfate (24 mg, 0.070 mmol) was added followed by dichloromethane.Stirring 5 min gave a clear biphasic solution. Iodomethyl methylcarbonate (19.5 mg, 0.091 mmol) was added as a solution indichloromethane. Stirring 3 hours gave complete reaction. The reactionwas diluted with water, dichloromethane, extracted with dichloromethane,washed with sodium bicarbonate, brine, dried over sodium sulfate, andpurified by silica-gel chromatography (1-12% methanol/dichloromethanegradient elution) to give the title compound. ¹H NMR (CDCl₃) δ 10.21 (m,1H), 8.44, (s, 1H), 7.32 (m, 1H), 6.80 (m, 2H), 5.88 (d, J=6.8 Hz, 1H),5.79 (d, J=6.4 Hz, 1H), 5.31 (m, 1H), 4.49 (d, J=6 Hz, 2H), 4.43-4.32(m, 3H), 3.92 (m, 1H), 3.81 (s, 3H), 3.67 (m, 1H), 1.39 (d, J=6.4 Hz,3H). ES⁺ MS: 494 (M+1).

Example 2{[(3S,11aR)-8-({[(2,4-Difluorophenyl)methyl]amino}carbonyl)-3-methyl-5,7-dioxo-2,3,5,7,11,11a-hexahydro[1,3]oxazolo[3,2-a]pyrido[1,2-d]pyrazin-6-yl]oxy}methyl2-(methyloxy)ethyl carbonate

The title compound was prepared from iodomethyl 2-(methyloxy)ethylcarbonate (122 mg, 0.468 mmol), 1b (50 mg, 0.117 mmol), potassiumcarbonate (48 mg, 0.351 mmol), and tetrabutylammonium hydrogen sulfate(40 mg, 0.117 mmol), using a similar process to that described inexample 1. ¹H NMR (CDCl₃) δ 10.20 (m, 1H), 8.42 (s, 1H), 7.34 (m, 1H),6.80 (m, 2H), 5.94 (d, J=6.8 Hz, 1H), 5.87 (d, J=6.4 Hz, 1H), 5.30 (dd,J=10, 4 Hz, 1H), 4.59 (m, 2H), 4.43-4.29 (m, 5H), 3.92 (m, 3H),3.70-3.61 (m, 3H), 3.36 (s, 3H), 1.40 (d, J=6 Hz, 3H). ES⁺ MS: 538(M+1).

Example 3{[(3S,11aR)-8-({[(2,4-Difluorophenyl)methyl]amino}carbonyl-3-methyl-5,7-dioxo-2,3,5,7,11,11a-hexahydro[1,3]oxazolo[3,2-a]pyrido[1,2-d]pyrazin-6-yl]oxy}methyl1-methylethyl carbonate

The title compound was prepared from iodomethyl 1-methylethyl carbonate(140 mg, 0.574 mmol), 1b (50 mg, 0.117 mmol), potassium carbonate (48mg, 0.351 mmol), and tetrabutylammonium hydrogen sulfate (40 mg, 0.117mmol), using a similar process to that described in example 1. ¹H NMR(CDCl₃) δ 10.29 (m, 1H), 8.44 (s, 1H), 7.29 (m, 1H), 6.77 (m, 2H), 5.84(s, 2H), 5.27 (dd, J=9.6, 3.6 Hz, 1H), 4.88 (m, 1H), 4.56 (m, 2H),4.40-4.29 (m, 3H), 3.89 (m, 1H), 3.65 (m, 1H), 1.37 (d, J=6.4 Hz, 3H)1.26 (m, 6H). ES⁺ MS: 522 (M+1).

Example 4{[(3S,11aR)-8-({[(2,4-Difluorophenyl)methyl]amino}carbonyl)-3-methyl-5,7-dioxo-2,3,5,7,11,11a-hexahydro[1,3]oxazolo[3,2-a]pyrido[1,2-d]pyrazin-6-yl]oxy}methyl2-{[2-(methyloxy)ethyl]oxy}ethyl carbonate

The title compound was prepared from iodomethyl2-{[2-(methyloxy)ethyl]oxy}ethyl carbonate (57 mg, 0.187 mmol), 1b (40mg, 0.094 mmol), potassium carbonate (39 mg, 0.281 mmol), andtetrabutylammonium hydrogen sulfate (32 mg, 0.094 mmol), using a similarprocess to that described in example 1. ¹H NMR (CDCl₃) δ 10.21 (m, 1H),8.44 (s, 1H), 7.32 (m, 1H), 6.81 (m, 2H), 5.93 (d, J=6.4 Hz, 1H), 5.83(d, J=6.4 Hz, 1H), 5.30 (dd, J=10, 3.6 Hz, 1H), 4.59 (m, 2H), 4.43-4.27(m, 5H), 3.93 (m, 1H), 3.77-3.61 (m, 5H), 3.52 (m, 2H), 3.35 (s, 3H),1.38 (d, J=6.4 Hz, 3H). ES⁺ MS: 582 (M+1).

Example 5{[(3S,11aR)-8-({[(2,4-Difluorophenyl)methyl]amino}carbonyl-3-methyl-5,7-dioxo-2,3,5,7,11,11a-hexahydro[1,3]oxazolo[3,2-a]pyrido[1,2-d]pyrazin-6-yl]oxy}methyl2-hydroxyethyl carbonate

a){[(3S,11aR)-8-({[(2,4-Difluorophenyl)methyl]amino}carbonyl)-3-methyl-5,7-dioxo-2,3,5,7,11,11a-hexahydro[1,3]oxazolo[3,2-a]pyrido[1,2-d]pyrazin-6-yl]oxy}methyl2-[(phenylmethyl)oxy]ethyl carbonate. The benzyl protected derivativewas prepared from iodomethyl 2-[(phenylmethyl)oxy]ethyl carbonate (126mg, 0.374 mmol), 1b (80 mg, 0.187 mmol), potassium carbonate (78 mg,0.562 mmol), and tetrabutylammonium hydrogen sulfate (64 mg, 0.187mmol), using a similar process to that described in example 1. ¹H NMR(CDCl₃) δ 10.21 (m, 1H), 8.45 (s, 1H), 7.34-7.25 (m, 6H), 6.78 (m, 2H),5.92 (d, J=6.8 Hz, 1H), 5.82 (d, J=6.4 Hz, 1H), 5.26 (dd, J=10, 4 Hz,1H), 4.57-4.52 (m, 4H), 4.44-4.23 (m, 5H), 3.84 (m, 1H), 3.71 (m, 2H),3.60 (m, 1H), 1.33 (d, J=6 Hz, 3H). ES⁺ MS: 614 (M+1).b){[(3S,11aR)-8-({[(2,4-Difluorophenyl)methyl]amino}carbonyl)-3-methyl-5,7-dioxo-2,3,5,7,11,11a-hexahydro[1,3]oxazolo[3,2-a]pyrido[1,2-d]pyrazin-6-yl]oxy}methyl2-hydroxyethyl carbonate. The intermediate from step (a) (97 mg, 0.158mmol) was dissolved in methanol and 10 w.t. % palladium on carbon (97mg) was added under a nitrogen atmosphere. The mixture was stirred under50 psi hydrogen for 14 hours, filtered through celite, and the filtratewas concentrated under reduced pressure to yield the title compound as awhite solid. ¹H NMR (CDCl₃) δ 10.12 (m, 1H), 8.43 (s, 1H), 7.34 (m, 1H),6.82 (m, 2H), 6.02 (d, J=6.8 Hz, 1H), 5.90 (d, J=6.4 Hz, 1H), 5.29 (dd,J=10, 4 Hz, 1H), 4.67-4.52 (m, 3H), 4.40-4.35 (m, 3H), 4.23 (m, 1H),4.01-3.92 (m, 2H), 3.79 (m, 1H), 3.71-3.63 (m, 2H), 1.41 (d, J=5.6 Hz,3H). ES⁺ MS: 524 (M+1).

Example 6{[(3S,11aR)-8-({[(2,4-Difluorophenyl)methyl]amino}carbonyl-3-methyl-5,7-dioxo-2,3,5,7,11,11a-hexahydro[1,3]oxazolo[3,2-a]pyrido[1,2-d]pyrazin-6-yl]oxy}methyl2-(phosphonooxy)ethyl carbonate mono-sodium salt

a) 2-({Bis[(phenylmethyl)oxy]phosphoryl}oxy)ethyl{[(3S,11aR)-8-({[(2,4-difluorophenyl)methyl]amino}carbonyl)-3-methyl-5,7-dioxo-2,3,5,7,11,11a-hexahydro[1,3]oxazolo[3,2-a]pyrido[1,2-d]pyrazin-6-yl]oxy}methylcarbonate. Dibenzyl N, N-diisopropyl-phosphoramidite was added to amixture of{[(3S,11aR)-8-({[(2,4-difluorophenyl)methyl]amino}carbonyl)-3-methyl-5,7-dioxo-2,3,5,7,11,11a-hexahydro[1,3]oxazolo[3,2-a]pyrido[1,2-d]pyrazin-6-yl]oxy}methyl2-hydroxyethyl carbonate (49.4 mg, 0.094 mmol) and tetrazole (79 mg,1.13 mmol) in dichloromethane at ambient temperature and stirred 3hours. Additional dibenzyl N,N-diisopropyl-phosphoramidite (0.08 mL) wasadded and the mixture was stirred for 14 hours at ambient temperature.The reaction was cooled in an ice-water bath, and m-CPBA (130 mg, 0.755mmol) was added carefully and the mixture was stirred for 30 minutesletting the ice-bath expire. Sodium thiosulfate solution was added, andthe mixture was extracted with dichloromethane, washed with sodiumbicarbonate solution and brine, and dried over sodium sulfate.Purification by silica gel chromatography afforded the title compound asa colorless residue. ¹H NMR (CDCl₃) δ 10.17 (m, 1H), 8.28 (s, 1H),7.35-7.23 (m, 11H), 6.78 (m, 2H), 5.95 (d, J=6.4 Hz, 1H), 5.89 (d, J=6.4Hz, 1H), 5.20 (dd, J=10, 3.6 Hz, 1H), 5.03-4.60 (m, 3H), 4.58 (m, 1H),4.45-4.12 (m, 5H), 3.73 (m, 1H), 3.58 (m, 1H), 1.30 (d, J=6.4 Hz, 3H).ES⁺ MS: 784 (M+1).b){[(3S,11aR)-8-({[(2,4-Difluorophenyl)methyl]amino}carbonyl)-3-methyl-5,7-dioxo-2,3,5,7,11,11a-hexahydro[1,3]oxazolo[3,2-a]pyrido[1,2-d]pyrazin-6-yl]oxy}methyl2-(phosphonooxy)ethyl carbonate. Intermediate from step a (26 mg, 0.033mmol), was dissolved in methanol, and 10 w.t. % palladium on carbon (26mg) was added and the reaction was stirred under 1 atm hydrogen for 30minutes. The mixture was filtered through Celite and concentrated underreduced pressure to yield the title compound as a white solid. ¹H NMR(DMSO-d₆) δ 10.26 (m, 1H), 8.58 (s, 1H), 7.40 (m, 1H), 7.21 (m, 1H),7.06 (m, 1H), 5.79 (d, J=6.4 Hz, 1H), 5.33 (d, J=6.4 Hz, 1H), 5.36 (dd,J=9.6, 3.2 Hz, 1H), 4.82 (m, 1H), 4.53 (m, 2H), 4.34-4.16 (m, 4H),4.08-3.94 (m, 3H), 3.63 (m, 1H), 1.25 (d, J=6 Hz, 3H). ES⁺ MS: 604(M+1).c){[(3S,11aR)-8-({[(2,4-Difluorophenyl)methyl]amino}carbonyl)-3-methyl-5,7-dioxo-2,3,5,7,11,11a-hexahydro[1,3]oxazolo[3,2-a]pyrido[1,2-d]pyrazin-6-yl]oxy}methyl2-(phosphonooxy)ethyl carbonate mono-sodium salt. Sodium hydroxide (0.44mL, 0.44 mmol, 1N aqueous solution) was added dropwise to a solution of{[(3S,11aR)-8-({[(2,4-difluorophenyl)methyl]amino}carbonyl)-3-methyl-5,7-dioxo-2,3,5,7,11,11a-hexahydro[1,3]oxazolo[3,2-a]pyrido[1,2-d]pyrazin-6-yl]oxy}methyl2-(phosphonooxy)ethyl carbonate prepared as described in step b (266 mg,0.441 mmol) in ethanol at 0° C. and the mixture was stirred 1 hourletting the ice bath expire. The mixture was triturated with diethylether and the solids were collected by vacuum filtration to yield thetitle compound as an orange solid. ¹H NMR (DMSO-d₆) δ 10.27 (m, 1H),8.58 (s, 1H), 7.42 (m, 1H), 7.24 (m, 1H), 7.07 (m, 1H), 5.78 (m, 1H),5.63 (m, 1H), 5.39 (m, 1H), 4.80 (m, 1H), 4.54 (m, 2H), 4.32-4.06 (m,4H), 3.80-3.60 (m, 3H), 3.40 (m, 1H, under DMSO), 1.26 (d, J=5.2 Hz,3H). ES⁺ MS: 604 (M+1).

Example 7{[(3S,11aR)-8-({[(2,4-Difluorophenyl)methyl]amino}carbonyl)-3-methyl-5,7-dioxo-2,3,5,7,11,11a-hexahydro[1,3]oxazolo[3,2-a]pyrido[1,2-d]pyrazin-6-yl]oxy}methyl3-hydroxypropyl carbonate

a){[(3S,11aR)-8-({[(2,4-Difluorophenyl)methyl]amino}carbonyl)-3-methyl-5,7-dioxo-2,3,5,7,11,11a-hexahydro[1,3]oxazolo[3,2-a]pyrido[1,2-d]pyrazin-6-yl]oxy}methyl3-[(phenylmethyl)oxy]propyl carbonate. The title compound was preparedin 95% yield according to example 1 from 1b (1.00 g, 2.34 mmol),iodomethyl 3-[(phenylmethyl)oxy]propyl carbonate (3.24 g, 9.25 mmol),potassium carbonate (1.97 g, 14.3 mmol) and tetrabutylammonium hydrogensulfate (1.30 g, 3.83 mmol). ¹H NMR (400 MHz, CDCl₃) δ ppm 10.18 (t,J=5.7 Hz, 1H), 8.37 (s, 1H), 7.35-7.20 (m, 6H), 6.83-6.72 (m, 2H), 5.92(d, J=6.6 Hz, 1H), 5.83 (d, J=6.6 Hz, 1H), 5.25 (dd, J=9.9, 3.8 Hz, 1H),4.65-4.50 (m, 2H), 4.46 (s, 2H), 4.37-4.22 (m, 5H), 3.86 (dd, J=12.2,10.0 Hz, 1H), 3.62 (dd, J=8.5, 6.9 Hz, 1H), 3.55 (t, J=6.2 Hz, 2H),2.04-1.92 (m, 2H), 1.34 (d, J=6.2 Hz, 3H); ES⁺ MS: 628 (M+1).b){[(3S,11aR)-8-({[(2,4-Difluorophenyl)methyl]amino}carbonyl)-3-methyl-5,7-dioxo-2,3,5,7,11,11a-hexahydro[1,3]oxazolo[3,2-a]pyrido[1,2-d]pyrazin-6-yl]oxy}methyl3-hydroxypropyl carbonate. A solution of the intermediate from step a(1.35 g, 2.15 mmol) in 40 mL of 1:1 THF/MeOH was subjected tohydrogenation at 55 psi in the presence of 10% palladium on charcoal(1.0 g, Degussa type). After 3 hours the reaction vessel was purged withnitrogen, catalyst removed by filtration through celite, and thefiltrate concentrated to dryness at reduced pressure to afford a whitesolid. This material was suspended in 10 mL of ethyl acetate and stirredwith addition of approximately 60 mL of hexane. The resulting whitesuspension was stirred overnight at RT. The solid was collected byvacuum filtration and dried under vacuum to afford the title compound(1.09 g, 94%) as a fluffy white solid. ¹H NMR (400 MHz, CDCl₃) δ ppm10.14 (t, J=5.6 Hz, 1H), 8.41 (s, 1H), 7.36-7.27 (m, 1H), 6.84-6.73 (m,2H), 5.93 (d, J=6.7 Hz, 1H), 5.85 (d, J=6.7 Hz, 1H), 5.27 (dd, J=9.9,3.7 Hz, 1H), 4.65-4.51 (m, 2H), 4.45-4.25 (m, 5H), 3.91 (dd, J=12.1,10.1 Hz, 1H), 3.74 (t, J=5.8, 2 H), 3.65 (dd, J=8.1, 6.8 Hz, 1H),1.96-1.83 (m, 2H), 1.37 (d, J=6.0 Hz, 3H); ES⁺ MS: 538 (M+1).

Example 8{[(3S,11aR)-8-({[(2,4-Difluorophenyl)methyl]amino}carbonyl)-3-methyl-5,7-dioxo-2,3,5,7,11,11a-hexahydro[1,3]oxazolo[3,2-a]pyrido[1,2-d]pyrazin-6-yl]oxy}methyl3-(phosphonooxy)propyl carbonate mono-sodium salt

a) 3-({Bis[(phenylmethyl)oxy]phosphoryl}oxy)propyl{[(3S,11aR)-8-({[(2,4-difluorophenyl)methyl]amino}carbonyl)-3-methyl-5,7-dioxo-2,3,5,7,11,11a-hexahydro[1,3]oxazolo[3,2-a]pyrido[1,2-d]pyrazin-6-yl]oxy}methylcarbonate. According to example 8,{[(3S,11aR)-8-({[(2,4-difluorophenyl)methyl]amino}carbonyl)-3-methyl-5,7-dioxo-2,3,5,7,11,11a-hexahydro[1,3]oxazolo[3,2-a]pyrido[1,2-d]pyrazin-6-yl]oxy}methyl3-hydroxypropyl carbonate (0.400 g, 0.744 mmol) was converted to thetitle compound in 93% yield using tetrazole (0.313 g, 4.47 mmol),dibenzyl N,N-diisopropyl-phosphoramidite (0.771 g, 2.23 mmol), andm-CPBA (0.642 g, 3.72 mmol). ¹H NMR (400 MHz, CDCl₃) δ ppm 10.17 (t,J=5.6 Hz, 1H), 8.33 (s, 1H), 7.37-7.24 (m, 11H), 6.83-6.72 (m, 2H), 5.92(d, J=6.6 Hz, 1H), 5.85 (d, J=6.6 Hz, 1H), 5.21 (dd, J=9.9, 3.7 Hz, 1H),5.05-4.92 (m, 4H), 4.65-4.51 (m, 2H), 4.40-4.01 (m, 7H), 3.80 (dd,J=12.1, 10.1 Hz, 1H), 3.59 (dd, J=8.6, 7.0 Hz, 1H), 2.09-1.88 (m, 2H),1.31 (d, J=6.2 Hz, 3H); ES⁺ MS: 798 (M+1).b){[(3S,11aR)-8-({[(2,4-Difluorophenyl)methyl]amino}carbonyl)-3-methyl-5,7-dioxo-2,3,5,7,11,11a-hexahydro[1,3]oxazolo[3,2-a]pyrido[1,2-d]pyrazin-6-yl]oxy}methyl3-(phosphonooxy)propyl carbonate. A solution of the intermediate fromstep a (0.544 g, 0.682 mmol) in 40 mL of methanol was subjected tohydrogenation at 35 psi in the presence of 10% Pd on carbon (100 mg).After 3 hours the reaction vessel was purged with nitrogen, catalystremoved by filtration through celite, and the filtrate concentrated todryness at reduced pressure to afford the title compound (0.399 g, 95%)as a white foam. ¹H NMR (400 MHz, CD₃OD) δ ppm 8.51 (s, 1H), 7.43-7.35(m, 1H), 6.98-6.84 (m, 2H), 5.79 (d, J=6.6 Hz, 1H), 5.68 (d, J=6.7 Hz,1H), 5.38 (dd, J=9.9, 3.7 Hz, 1H), 4.65 (dd, J=12.4, 3.7 Hz, 1H), 4.58(s, 2H), 4.41-4.30 (m, 2H), 4.28-4.16 (m, 2H), 4.08-3.97 (m, 3H),3.72-3.63 (m, 1H), 2.07-1.88 (m, 2H), 1.35 (d, J=5.9 Hz, 3H); ES⁺ MS:618 (M+1).c){[(3S,11aR)-8-({[(2,4-Difluorophenyl)methyl]amino}carbonyl)-3-methyl-5,7-dioxo-2,3,5,7,11,11a-hexahydro[1,3]oxazolo[3,2-a]pyrido[1,2-d]pyrazin-6-yl]oxy}methyl3-(phosphonooxy)propyl carbonate mono-sodium salt. To a stirredsuspension of the intermediate from step b (0.389 g, 0.630 mmol) in 25mL of water was added sodium bicarbonate (53 mg, 0.630 mmol) dissolvedin 3 mL of water. The solid slowly dissolved affording a slightly turbidlight yellow solution. The aqueous solution was filtered through celiteand the filtrate concentrated to approximately 10 mL by rotaryevaporation. The solution was then stirred while 50 mL of EtOH was addeddropwise via addition funnel over 10 minutes. A white suspension wasproduced that was stirred at RT for 1 hour. The solid was collected byfiltration and dried under vacuum to afford the title compound (0.27 g,67%) as a white powder. ¹H NMR (400 MHz, D₂O) δ ppm 8.33 (s, 1H),7.24-7.13 (m, 1H), 6.84-6.71 (m, 2H), 5.62 (d, J=6.9 Hz, 1H), 5.41 (d,J=6.9 Hz, 1H), 5.33 (dd, J=10.1, 3.7 Hz, 1H), 4.52 (dd, J=12.4, 3.6 Hz,1H), 4.38 (s, 2H), 4.32-4.19 (m, 2H), 4.16-4.03 (m, 2H), 3.98 (dd,J=11.8, 10.6 Hz, 1H), 3.76-3.58 (m, 3H), 1.84-1.71 (m, 2H), 1.19 (d,J=6.0 Hz, 3H); ES⁺ MS: 618 (M+1).

Example 9{[(3S,11aR)-8-({[(2,4-Difluorophenyl)methyl]amino}carbonyl)-3-methyl-5,7-dioxo-2,3,5,7,11,11a-hexahydro[1,3]oxazolo[3,2-a]pyrido[1,2-d]pyrazin-6-yl]oxy}methyl4-nitrophenyl carbonate

a) Chloromethyl 4-nitrophenyl carbonate. N-methyl morpholine (1.24 mL,11.24 mmol) was added dropwise to a solution of 4-nitrophenol (1.56 g,11.24 mmol) in dichloromethane at 0° C., followed by dropwise additionof chloromethyl chloridocarbonate (1 mL, 11.24 mmol) and the mixture wasstirred for 14 hours at ambient temperature. The reaction was dilutedwith citric acid solution, extracted with dichloromethane, washed withaqueous sodium bicarbonate, brine, and dried over sodium sulfate toyield the title compound as a yellow oil. ¹H NMR (CDCl₃) δ 8.29 (m, 2H),7.40 (m, 2H), 5.82 (s, 2H).b) Iodomethyl 4-nitrophenyl carbonate. Chloromethyl 4-nitrophenylcarbonate (2.47 g, 10.67 mmol), sodium iodide (1.76 g, 11.73 mmol) weresuspended in acetone and heated overnight at 45° C. The yellowsuspension was allowed to cool to ambient temperature, concentratedunder reduced pressure, diluted with water and aqueous sodiumthiosulfate, extracted with dichloromethane, washed with brine, driedover sodium sulfate, and concentrated under reduced pressure to give thetitle compound as a clear yellow oil. ¹H NMR (CDCl₃) δ 8.30 (dd, J=7.2,2.4 Hz, 2H), 7.42 (dd, J=6.8, 2 Hz, 2H), 6.06 (s, 2H).c){[(3S,11aR)-8-({[(2,4-Difluorophenyl)methyl]amino}carbonyl)-3-methyl-5,7-dioxo-2,3,5,7,11,11a-hexahydro[1,3]oxazolo[3,2-a]pyrido[1,2-d]pyrazin-6-yl]oxy}methyl4-nitrophenyl carbonate. The nitrophenyl carbonate derivative wasprepared from(3S,11aR)—N-[(2,4-difluorophenyl)methyl]-6-hydroxy-3-methyl-5,7-dioxo-2,3,5,7,11,11a-hexahydro[1,3]oxazolo[3,2-a]pyrido[1,2-d]pyrazine-8-carboxamidesodium salt (50 mg, 0.117 mmol), iodomethyl 4-nitrophenyl carbonate (76mg, 0.234 mmol), potassium carbonate (49 mg, 0.351 mmol), andtetrabutylammonium hydrogen sulfate (40 mg, 0.117 mmol) in a mannersimilar to that described in example 1, step c. The compound was isolateas an impure mixture that was carried on without further purification.¹H NMR (CDCl₃) δ 10.17 (m, 1H), 8.16 (s, 1H), 8.28 (m, 2H), 7.52 (m,2H), 7.34 (m, 1H), 6.79 (m, 2H), 6.04 (d, J=6.8 Hz, 1H), 5.59 (d, J=6.8Hz, 1H), 5.32 (dd, J=9.6, 3.6 Hz, 1H), 4.60 (m, 2H), 4.45-4.36 (m, 3H),3.95 (m, 1H), 3.71 (m, 1H), 1.40 (d, J=5.6 Hz, 3H). ES⁺ MS: 601 (M+1).

Example 10{[(3S,11aR)-8-({[(2,4-Difluorophenyl)methyl]amino}carbonyl)-3-methyl-5,7-dioxo-2,3,5,7,11,11a-hexahydro[1,3]oxazolo[3,2-a]pyrido[1,2-d]pyrazin-6-yl]oxy}methyl2-pyridinylmethyl carbonate

To a solution of{[(3S,11aR)-8-({[(2,4-difluorophenyl)methyl]amino}carbonyl)-3-methyl-5,7-dioxo-2,3,5,7,11,11a-hexahydro[1,3]oxazolo[3,2-a]pyrido[1,2-d]pyrazin-6-yl]oxy}methyl4-nitrophenyl carbonate (88 mg, 0.146 mmol) in acetonitrile (10 mL) wasadded 2-pyridinylmethanol (0.01 mL, 0.146 mmol) triethylamine (0.06 mL,0.439 mmol) and DMAP (18 mg, 0.146 mmol). The resultant mixture wasstirred at rt for 3 h. Standard aqueous workup followed by purificationby reverse-phase hplc afforded the title compound as the TFA salt whichwas suspended in dichloromethane and washed with aqueous sodiumbicarbonate and dried over sodium sulfate. Purification by silica-gelchromatography yielded the title compound as a white solid. ¹H NMR(CDCl₃) δ 10.16 (m, 1H), 8.53 (d, J=4.8 Hz, 1H), 8.38 (s, 1H), 7.65 (m,1H), 7.46 (d, J=8 Hz, 1H), 7.32 (m, 1H), 7.19 (m, 1H), 6.76 (m, 2H),5.97 (d, J=6.8 Hz, 1H), 5.87 (d, J=6.4 Hz, 1H), 5.31-5.25 (m, 3H), 4.56(m, 2H), 4.37-4.24 (m, 3H), 3.89 (m, 1H), 3.64 (m, 1H), 1.34 (d, J=6 Hz,3H). ES⁺ MS: 571 (M+1).

Example 11{[(3S,11aR)-8-({[(2,4-Difluorophenyl)methyl]amino}carbonyl)-3-methyl-5,7-dioxo-2,3,5,7,11,11a-hexahydro[1,3]oxazolo[3,2-a]pyrido[1,2-d]pyrazin-6-yl]oxy}methyl2-(2-oxo-1-pyrrolidinyl)ethyl carbonate

The title compound was prepared from{[(3S,11aR)-8-({[(2,4-difluorophenyl)methyl]amino}carbonyl)-3-methyl-5,7-dioxo-2,3,5,7,11,11a-hexahydro[1,3]oxazolo[3,2-a]pyrido[1,2-d]pyrazin-6-yl]oxy}methyl4-nitrophenyl carbonate (50 mg, 0.83 mmol),1-(2-hydroxyethyl)-2-pyrrolidinone (9 μL, 0.083 mmol), triethylamine (35μL, 0.250 mmol), and DMAP (10 mg, 0.083 mmol), in a process similar tothat described in example 10. Purification by silica-gel chromatographyand reverse-phase hplc afforded the title compound as a white solid. ¹HNMR (CDCl₃) δ 10.28 (m, 1H), 8.45 (s, 1H), 7.32 (m, 1H), 6.80 (m, 2H),5.93 (d, J=6.8 Hz, 1H), 5.80 (d, J=6.4 Hz, 1H), 5.28 (dd, J=10, 3.6 Hz,1H), 4.64-4.23 (m, 8H), 3.94 (m, 1H), 3.68-3.50 (m, 4H), 2.42 (t, J=8Hz, 2H), 2.02 (m, 2H), 1.37 (d, J=6 Hz, 3H). ES⁺ MS: 591 (M+1).

Example 12{[(3S,11aR)-8-({[(2,4-Difluorophenyl)methyl]amino}carbonyl)-3-methyl-5,7-dioxo-2,3,5,7,11,11a-hexahydro[1,3]oxazolo[3,2-a]pyrido[1,2-d]pyrazin-6-yl]oxy}methyl2-(4-morpholinyl)ethyl carbonate hydrochloric acid salt

{[(3S,11aR)-8-({[(2,4-Difluorophenyl)methyl]amino}carbonyl)-3-methyl-5,7-dioxo-2,3,5,7,11,11a-hexahydro[1,3]oxazolo[3,2-a]pyrido[1,2-d]pyrazin-6-yl]oxy}methyl2-(4-morpholinyl)ethyl carbonate hydrochloric acid salt. The titlecompound was prepared from{[(3S,11aR)-8-({[(2,4-difluorophenyl)methyl]amino}carbonyl)-3-methyl-5,7-dioxo-2,3,5,7,11,11a-hexahydro[1,3]oxazolo[3,2-a]pyrido[1,2-d]pyrazin-6-yl]oxy}methyl4-nitrophenyl carbonate (121 mg, 0.202 mmol), 2-(4-morpholinyl)ethanol(excess), triethylamine (0.08 mL, 0606 mmol), and DMAP (50 mg, 0.400mmol), in a process similar to that described in example 10.Purification by silica-gel chromatography and reverse-phase hplc,followed by an aqueous sodium bicarbonate wash afforded the titlecompound as a white solid. Intermediate prepared as described above (33mg, 0.056 mmol) was dissolved in ethanol and cooled in an ice-waterbath. A 1 normal hydrochloric acid solution (0.06 mL) was added dropwiseand the reaction was stirred 3 hours at ambient temperature. The mixturewas cooled to 0° C. and triturated with diethyl ether and the solid wascollected by vacuum filtration. Recrystallization from amethanol/dichloromethane/ethyl acetate mixture afforded the titlecompound as a white crystalline solid. ¹H NMR (methanol-d₄/CDCl₃) δ10.17 (m, 1H), 8.31 (s, 1H), 7.27 (m, 1H), 6.77 (m, 2H), 5.98 (d, J=6.8Hz, 1H), 5.72 (d, J=6.8 Hz, 1H), 5.24 (dd, J=9.6, 3.6 Hz, 1H), 4.70-4.35(m, 8H), 4.11-3.90 (m, 3H), 3.65 (m, 1H), 3.45-3.32 (m, 3H), 3.06 (m,1H), 2.70-2.50 (m, 3H), 1.32 (d, J=6.4 Hz, 3H). ES⁺ MS: 593 (M+1).

Example 13 Phenylmethyl({[({[(3S,11aR)-8-({[(2,4-difluorophenyl)methyl]amino}carbonyl)-3-methyl-5,7-dioxo-2,3,5,7,11,11a-hexahydro[1,3]oxazolo[3,2-a]pyrido[1,2-d]pyrazin-6-yl]oxy}methyl)oxy]carbonyl}oxy)acetate

The title compound was prepared from phenylmethyl({[(iodomethyl)oxy]carbonyl}oxy)acetate (819 mg, 2.34 mmol), 1b (500 mg,1.17 mmol), potassium carbonate (485 mg, 3.51 mmol), andtetrabutylammonium hydrogen sulfate (397 mg, 1.17 mmol), using a similarprocess to that described in example 1. ¹H NMR (CDCl₃) δ 10.18 (m, 1H),8.36 (s, 1H), 7.34-7.27 (m, 6H), 6.76 (m, 2H), 5.98 (d, J=6.8 Hz, 1H),5.85 (d, J=6.4 Hz, 1H), 5.27 (dd, J=10, 4 Hz, 1H), 5.15 (s, 2H), 4.66(s, 2H), 4.60 (m, 2H), 4.39-4.23 (m, 3H), 3.88 (m, 1H), 3.64 (m, 1H),1.35 (d, J=6.4 Hz, 3H). ES⁺ MS: 628 (M+1).

Example 14({[({[(3S,11aR)-8-({[(2,4-Difluorophenyl)methyl]amino}carbonyl-3-methyl-5,7-dioxo-2,3,5,7,11,11a-hexahydro[1,3]oxazolo[3,2-a]pyrido[1,2-d]pyrazin-6-yl]oxy}methyl)oxy]carbonyl}oxy)aceticacid sodium salt

a)({[({[(3S,11aR)-8-({[(2,4-Difluorophenyl)methyl]amino}carbonyl)-3-methyl-5,7-dioxo-2,3,5,7,11,11a-hexahydro[1,3]oxazolo[3,2-a]pyrido[1,2-d]pyrazin-6-yl]oxy}methyl)oxy]carbonyl}oxy)aceticacid. Phenylmethyl({[({[(3S,11aR)-8-({[(2,4-difluorophenyl)methyl]amino}carbonyl)-3-methyl-5,7-dioxo-2,3,5,7,11,11a-hexahydro[1,3]oxazolo[3,2-a]pyrido[1,2-d]pyrazin-6-yl]oxy}methyl)oxy]carbonyl}oxy)acetate(prepared as described in example 17) (247 mg, 0.394 mmol) 10 w.t. %palladium on carbon (190 mg) were stirred in an ethyl acetate/methanolmixture under 1 atm hydrogen atmosphere for 30 minutes. The reaction wasfiltered through celite and concentrated under reduced pressure to yielda white solid. ¹H NMR (CDCl₃) δ 10.28 (m, 1H), 8.32 (s, 1H), 7.28 (m,1H), 6.76 (m, 2H), 5.92 (d, J=6.4 Hz, 1H), 5.86 (d, J=6.4 Hz, 1H), 5.28(dd, J=10, 3.2 Hz, 1H), 4.55 (br s, 4H), 4.37-4.28 (m, 3H), 3.91 (m,1H), 3.63 (m, 1H), 3.35 (m, 1H), 1.34 (d, J=6 Hz, 3H). ES⁺ MS: 538(M+1).b)({[({[(3S,11aR)-8-({[(2,4-Difluorophenyl)methyl]amino}carbonyl)-3-methyl-5,7-dioxo-2,3,5,7,11,11a-hexahydro[1,3]oxazolo[3,2-a]pyrido[1,2-d]pyrazin-6-yl]oxy}methyl)oxy]carbonyl}oxy)aceticacid sodium salt. The solid prepared as described in step (a) (200 mg,0.372 mmol) was dissolved in dioxane and cooled in an ice-water bath.Sodium hydroxide (0.37 mL, 1 normal solution) was added and the ice bathwas removed and the mixture was stirred 10 minutes. Concentration underreduced pressure afforded the title compound as a white solid. ¹H NMR(dmso-d₆) δ 10.28 (m, 1H), 8.57 (s, 1H), 7.39 (m, 1H), 7.23 (m, 1H),7.06 (m, 1H), 5.74 (d, J=6.8 Hz, 1H), 5.60 (d, J=6.8 Hz, 1H), 5.39 (dd,J=10, 3.6 Hz, 1H), 4.80 (dd, J=12, 3.6 Hz, 1H), 4.53 (d, J=6 Hz, 2H),4.32 (m, 1H), 4.22 (m, 1H), 4.08-3.98 (m, 3H), 3.13 (m, 1H), 1.25 (d,J=6 Hz, 3H). ES⁺ MS: 538 (M+1).

Example 15{[(3S,11aR)-8-({[(2,4-Difluorophenyl)methyl]amino}carbonyl)-3-methyl-5,7-dioxo-2,3,5,7,11,11a-hexahydro[1,3]oxazolo[3,2-a]pyrido[1,2-d]pyrazin-6-yl]oxy}methyl2-(dimethylamino)ethyl carbonate trifluoroacetic acid salt

The title compound was prepared from{[(3S,11aR)-8-({[(2,4-difluorophenyl)methyl]amino}carbonyl)-3-methyl-5,7-dioxo-2,3,5,7,11,11a-hexahydro[1,3]oxazolo[3,2-a]pyrido[1,2-d]pyrazin-6-yl]oxy}methyl4-nitrophenyl carbonate 100 mg, 0.167 mmol 2-(dimethylamino)ethanol(excess), triethylamine (0.02 mL, 0.167 mmol), and DMAP (20 mg, 0.167mmol), in a process similar to that described in example 10.Purification by reverse-phase hplc, afforded the title compound as awhite solid consisting of the trifluoroacetate salt from the TFA in themobile phase. NMR (CDCl₃) δ 10.19 (m, 1H), 8.46 (s, 1H), 7.33 (m, 1H),6.81 (m, 2H), 5.98 (d, J=6.8 Hz, 1H), 5.80 (d, J=6.8 Hz, 1H), 5.27 (dd,J=10, 3.6 Hz, 1H), 4.65-4.33 (m, 7H), 4.60 (m, 1H), 3.66 (m, 1H), 3.46(m, 2H), 2.92 (m, 6H), 1.35 (d, J=6 Hz, 3H). ES⁺ MS: 551 (M+1).

Example 16{[(3S,11aR)-8-({[(2,4-Difluorophenyl)methyl]amino}carbonyl)-3-methyl-5,7-dioxo-2,3,5,7,11,11a-hexahydro[1,3]oxazolo[3,2-a]pyrido[1,2-d]pyrazin-6-yl]oxy}methyl2-oxo-2-{4-[2-(1-pyrrolidinyl)ethyl]-1-piperazinyl}ethyl carbonatedi-hydrochloride

{[({[(3S,11aR)-8-({[(2,4-Difluorophenyl)methyl]amino}carbonyl)-3-methyl-5,7-dioxo-2,3,5,7,11,11a-hexahydro[1,3]oxazolo[3,2-a]pyrido[1,2-d]pyrazin-6-yl]oxy}methyl2-oxo-2-{4-[2-(1-pyrrolidinyl)ethyl]-1-piperazinyl}ethyl carbonatedi-hydrochloride. A mixture of({[({[(3S,11aR)-8-({[(2,4-difluorophenyl)methyl]amino}carbonyl)-3-methyl-5,7-dioxo-2,3,5,7,11,11a-hexahydro[1,3]oxazolo[3,2-a]pyrido[1,2-d]pyrazin-6-yl]oxy}methyl)oxy]carbonyl}oxy)aceticacid (60 mg, 0.112 mmol) (prepared as described in example 14, step(a)), 1-[2-(1-pyrrolidinyl)ethyl]piperazine (31 mg, 0.167 mmol),N,N-diisopropylethylamine (0.03 mL, 0.167 mmol), and HATU (64 mg, 0.167mmol) were stirred in DMF for 1 hour. The mixture was diluted withbrine, extracted with dichloromethane, washed with brine, and dried oversodium sulfate.

The product from step (a) was dissolved in a minimal amount ofdichloromethane, diluted with ethanol, and cooled in an ice-water bath.Hydrochloric acid (0.24 mL, 1 normal solution) was added and thereaction was stirred 15 minutes. Dichloromethane was partially removedunder reduced pressure and the mixture was cooled and triturated withdiethyl ether. The resultant solid was collected by vacuum filtration toyield the title compound as a yellow solid. ¹H NMR (dmso-d₆) δ 10.21 (m,1H), 8.55 (s, 1H), 7.36 (m, 1H), 7.22 (m, 1H), 7.03 (m, 1H), 5.78 (d,J=6.4 Hz, 1H), 5.61 (d, J=6.4 Hz, 1H), 5.33 (dd, J=9.6, 3.2 Hz, 1H),4.78 (m, 2H), 4.49 (m, 1H), 4.27 (m, 1H), 4.19 (m, 1H), 3.99 (m, 1H),3.70-3.10 (m, 19H), 2.62-2.80 (m, 2H), 1.89 (br s, 2H), 1.22 (d, J=6 Hz,3H). ES⁺ MS: 703 (M+1).

Example 17 Methyl({[({[(3S,11aR)-8-({[(2,4-difluorophenyl)methyl]amino}carbonyl)-3-methyl-5,7-dioxo-2,3,5,7,11,11a-hexahydro[1,3]oxazolo[3,2-a]pyrido[1,2-d]pyrazin-6-yl]oxy}methyl)oxy]carbonyl}oxy)acetate

The title compound was prepared from methyl({[(iodomethyl)oxy]carbonyl}oxy)acetate (103 mg, 0.374 mmol), 1b (80 mg,0.187 mmol), potassium carbonate (78 mg, 0.5621 mmol), andtetrabutylammonium hydrogen sulfate (64 mg, 0.187 mmol), using a similarprocess to that described in example 1. ¹H NMR (CDCl₃) δ 10.20 (m, 1H),8.39 (s, 1H), 7.33 (m, 1H), 6.78 (m, 2H), 6.00 (d, J=6.8 Hz, 1H), 5.88(d, J=6.8 Hz, 1H), 5.30 (dd, J=10, 4 Hz, 1H), 4.63-4.58 (m, 4H),4.43-4.28 (m, 4H), 3.93 (m, 1H), 3.73 (s, 2H), 3.66 (m, 1H), 1.38 (d,J=6 Hz, 3H). ES⁺ MS: 552 (M+1).

Example 18{[(3S,11aR)-8-({[(2,4-Difluorophenyl)methyl]amino}carbonyl-3-methyl-5,7-dioxo-2,3,5,7,11,11a-hexahydro[1,3]oxazolo[3,2-a]pyrido[1,2-d]pyrazin-6-yl]oxy}methyl2-oxo-2-[(2-pyridinylmethyl)amino]ethyl carbonate hydrochloric acid salt

a){[(3S,11aR)-8-({[(2,4-Difluorophenyl)methyl]amino}carbonyl)-3-methyl-5,7-dioxo-2,3,5,7,11,11a-hexahydro[1,3]oxazolo[3,2-a]pyrido[1,2-d]pyrazin-6-yl]oxy}methyl2-oxo-2-[(2-pyridinylmethyl)amino]ethyl carbonate. The title compoundwas prepared from({[({[(3S,11aR)-8-({[(2,4-difluorophenyl)methyl]amino}carbonyl)-3-methyl-5,7-dioxo-2,3,5,7,11,11a-hexahydro[1,3]oxazolo[3,2-a]pyrido[1,2-d]pyrazin-6-yl]oxy}methyl)oxy]carbonyl}oxy)aceticacid (64 mg, 0.119 mmol), (2-pyridinylmethyl)amine (0.02 mL, 0.179 mL),N,N-diisopropylethylamine (0.03 mL, 0.179 mL), and HATU (69 mg, 0.179mmol), using a process similar to that described in example 16, step(a). Purification by silica gel chromatography yielded the titlecompound as a white solid. ¹H NMR (CDCl₃) δ 10.09 (m, 1H), 8.46 (d,J=5.2 Hz, 1H), 8.38 (s, 1H), 7.75 (m, 1H), 7.59 (m, 1H), 7.34-7.26 (m,2H), 7.14 (m, 1H), 6.78 (m, 2H), 6.04 (d, J=6.8 Hz, 1H), 5.87 (d, J=6.8Hz, 1H), 5.27-5.22 (m, 2H), 4.80-4.52 (m, 5H), 4.32-4.22 (m, 3H), 3.82(m, 1H), 3.61 (m, 1H), 1.26 (d, J=6 Hz, 3H). ES⁺ MS: 628 (M+1).b){[(3S,11aR)-8-({[(2,4-Difluorophenyl)methyl]amino}carbonyl)-3-methyl-5,7-dioxo-2,3,5,7,11,11a-hexahydro[1,3]oxazolo[3,2-a]pyrido[1,2-d]pyrazin-6-yl]oxy}methyl2-oxo-2-[(2-pyridinylmethyl)amino]ethyl carbonate hydrochloric acidsalt. Product prepared as described in step (a) above (314 mg, 0.500mmol) was dissolved in dioxane and cooled in an ice-water bath.Hydrochloric acid (0.5 mL, 1N) was added and the mixture was stirred 15minutes at ambient temperature, then concentrated under reduced pressureto yield the title compound as a white solid. ¹H NMR (CDCl₃) δ 10.06 (m,1H), 8.57-8.46 (m, 2H), 8.42 (s, 1H), 8.28 (m, 1H), 7.96 (d, J=8 Hz,1H), 7.72 (m, 1H), 7.33 (m, 1H), 6.78 (m, 2H), 6.04 (d, J=6.8 Hz, 1H),5.70 (d, J=6.8 Hz, 1H), 5.31 (m, 1H), 5.09-5.03 (m, 2H), 4.85 (m, 1H),4.64-4.57 (m, 2H), 4.47 (m, 2H), 4.27 (m, 2H), 3.71-3.67 (m, 3H), 1.32(d, J=6 Hz, 3H). ES⁺ MS: 628 (M+1).

Example 19{[(3S,11aR)-8-({[(2,4-Difluorophenyl)methyl]amino}carbonyl)-3-methyl-5,7-dioxo-2,3,5,7,11,11a-hexahydro[1,3]oxazolo[3,2-a]pyrido[1,2-d]pyrazin-6-yl]oxy}methyl2-(4-methyl-1-piperazinyl)ethyl carbonate

The title compound was prepared from{[(3S,11aR)-8-({[(2,4-difluorophenyl)methyl]amino}carbonyl)-3-methyl-5,7-dioxo-2,3,5,7,11,11a-hexahydro[1,3]oxazolo[3,2-a]pyrido[1,2-d]pyrazin-6-yl]oxy}methyl4-nitrophenyl carbonate (200 mg, 0.333 mmol)2-(4-methyl-1-piperazinyl)ethanol (excess), triethylamine (0.05 mL,0.333 mmol), and DMAP (41 mg, 0.333 mmol), in a process similar to thatdescribed in example 10. Purification by reverse-phase hplc gave thetrifluoroacetic acid salt. The isolated solid was dissolved indichloromethane, washed with sodium bicarbonate and dried over sodiumsulfate to afford the title compound as a white solid. This product (70mg, 0.116 mmol) was suspended in EtOH and placed in an ice-water bath.Hydrochloric acid (0.23 mL, 1N) was added and the reaction was stirred30 minutes letting the ice bath expire. The mixture was triturated withdiethyl ether and the solid formed was collected by vacuum filtration.¹H NMR (CDCl₃) δ 10.15 (br s, 1H), 8.42 (s, 1H), 7.31 (m, 1H), 6.77 (m,2H), 6.00 (d, J=6.4 Hz, 1H), 5.76 (d, J=6.4 Hz, 1H), 5.25 (br s, 1H),4.67-4.05 (m, 8H), 3.80-3.30 (m, 11H), 2.83 (br s, 3H), 1.35 (br s, 3H).ES⁺ MS: 606 (M+1).

Example 20{[(3S,11aR)-8-({[(2,4-Difluorophenyl)methyl]amino}carbonyl)-3-methyl-5,7-dioxo-2,3,5,7,11,11a-hexahydro[1,3]oxazolo[3,2-a]pyrido[1,2-d]pyrazin-6-yl]oxy}methyl2-{[2-(4-morpholinyl)ethyl]amino}-2-oxoethyl carbonate trifluoroaceticacid salt

The title compound was prepared from({[({[(3S,11aR)-8-({[(2,4-difluorophenyl)methyl]amino}carbonyl)-3-methyl-5,7-dioxo-2,3,5,7,11,11a-hexahydro[1,3]oxazolo[3,2-a]pyrido[1,2-d]pyrazin-6-yl]oxy}methyl)oxy]carbonyl}oxy)aceticacid (59 mg, 0.110 mmol), [2-(4-morpholinyl)ethyl]amine (0.02 mL, 0.165mmol), N,N-diisopropylethylamine (0.03 mL, 0.65 mmol), and HATU (63 mg,0.165 mmol), using a process similar to that described in example 16,step (a). Purification by silica gel chromatography and reverse-phasehplc yielded the title compound as a white solid. ¹H NMR (CDCl₃) δ 10.11(m, 1H), 8.51 (s, 1H), 8.32 (m, 1H), 7.31 (m, 1H), 6.78 (m, 2H), 6.02(d, J=6.4 Hz, 1H), 5.49 (d, J=6.4 Hz, 1H), 5.31 (dd, J=10, 4 Hz, 1H),4.68-4.53 (m, 4H), 4.44-4.32 (m, 4H), 4.06 (m, 1H), 3.93-3.46 (m, 8H),3.23 (m, 2H), 2.86 (m, 2H), 1.34 (d, J=6 Hz, 3H). ES⁺ MS: 650 (M+1).

Example 21{[(3S,11aR)-8-({[(2,4-Difluorophenyl)methyl]amino}carbonyl)-3-methyl-5,7-dioxo-2,3,5,7,11,11a-hexahydro[1,3]oxazolo[3,2-a]pyrido[1,2-d]pyrazin-6-yl]oxy}methyl2-{[4-(dimethylamino)butyl]amino}-2-oxoethyl carbonate trifluoroaceticacid salt

The title compound was prepared from({[({[(3S,11aR)-8-({[(2,4-difluorophenyl)methyl]amino}carbonyl)-3-methyl-5,7-dioxo-2,3,5,7,11,11a-hexahydro[1,3]oxazolo[3,2-a]pyrido[1,2-d]pyrazin-6-yl]oxy}methyl)oxy]carbonyl}oxy)aceticacid (60 mg, 0.112 mmol), N-methyl-1,4-butanediamine (16 mg, 0.134mmol), N,N-diisopropylethylamine (0.03 mL, 0.167 mmol), and HATU (64 mg,0.167 mmol), using a process similar to that described in example 16,step (a). Purification reverse-phase hplc yielded the title compound asa white solid. ¹H NMR (CDCl₃) δ 11.23 (br s, 1H), 10.04 (m, 1H), 8.50(s, 1H), 7.84 (m, 1H), 7.32 (m, 1H), 6.79 (m, 2H), 6.00 (d, J=6.8 Hz,1H), 5.89 (m, 2H), 5.47 (d, J=6.8 Hz, 1H), 5.37 (dd, J=10, 3.6 Hz, 1H),4.71-0.431 (m, 6H), 4.04 (m, 1H), 3.68 (m, 1H), 3.52 (m, 1H), 3.02-2.91(m, 3H), 2.76 (m, 5H), 1.73-1.49 (m, 4H), 1.35 (d, J=5.6 Hz, 3H). ES⁺MS: 636 (M+1).

Example 22{[(3S,11aR)-8-({[(2,4-Difluorophenyl)methyl]amino}carbonyl)-3-methyl-5,7-dioxo-2,3,5,7,11,11a-hexahydro[1,3]oxazolo[3,2-a]pyrido[1,2-d]pyrazin-6-yl]oxy}methyl2-{[3-(1H-imidazol-1-yl)propyl]amino}-2-oxoethyl carbonate

The title compound was prepared from({[({[(3S,11aR)-8-({[(2,4-difluorophenyl)methyl]amino}carbonyl)-3-methyl-5,7-dioxo-2,3,5,7,11,11a-hexahydro[1,3]oxazolo[3,2-a]pyrido[1,2-d]pyrazin-6-yl]oxy}methyl)oxy]carbonyl}oxy)aceticacid (63 mg, 0.112 mmol), [3-(1H-imidazol-1-yl)propyl]amine (0.02 mL,0.176 mmol), N,N-diisopropylethylamine (0.03 mL, 0.176 mmol), and HATU(67 mg, 0.176 mmol), using a process similar to that described inexample 16, step (a). Purification by silica gel chromatography yieldedthe title compound as a white solid. ¹H NMR (CDCl₃) δ 10.04 (m, 1H),8.16 (s, 1H), 7.54 (m, 1H), 7.47 (s, 1H), 7.30 (m, 1H), 6.94 (s, 1H),6.87 (s, 1H), 6.77 (m, 2H), 6.00 (d, J=6.8 Hz, 1H), 5.65 (d, J=6.8 Hz,1H), 5.31-5.25 (m, 2H), 4.62-4.41 (m, 4H), 4.31 (m, 1H), 4.19 (m, 1H),4.01-3.29 (m, 3H), 3.02 (m, 1H), 3.36 (m, 1H), 3.03 (m, 1H), 1.97 (m,2H), 1.28 (d, J=6.4 Hz, 3H). ES⁺ MS:645 (M+1).

Example 23 2-Pyridinylmethyl({[({[(3S,11aR)-8-({[(2,4-difluorophenyl)methyl]amino}carbonyl)-3-methyl-5,7-dioxo-2,3,5,7,11,11a-hexahydro[1,3]oxazolo[3,2-a]pyrido[1,2-d]pyrazin-6-yl]oxy}methyl)oxy]carbonyl}oxy)acetatetrifluoroacetic acid salt

({[({[(3S,11aR)-8-({[(2,4-difluorophenyl)methyl]amino}carbonyl)-3-methyl-5,7-dioxo-2,3,5,7,11,11a-hexahydro[1,3]oxazolo[3,2-a]pyrido[1,2-d]pyrazin-6-yl]oxy}methyl)oxy]carbonyl}oxy)aceticacid (prepared as described in example 16, step (a)) (37 mg, 0.069mmol), 2-pyridinylmethanol (0.01 mL, 0.104 mmol), DMAP (8 mg, 0.069mmol), DCC (21 mg, 0.103 mmol) were stirred in dichloromethane 8 hours.Water was added and the mixture was extracted with dichloromethane,washed with sodium bicarbonate, brine, and dried over sodium sulfate.Purification by silica gel chromatography and reverse-phase hplc yieldedthe title compound as a white solid. ¹H NMR (CDCl₃) δ 10.31 (m, 1H),8.79 (d, J=4.8 Hz, 1H), 8.45 (s, 1H), 8.09 (m, 1H), 7.99-7.59 (m, 2H),7.31 (m, 1H), 6.78 (m, 2H), 5.97 (d, J=6.4 Hz, 1H), 5.83 (d, J=6.4 Hz,1H), 5.46 (s, 2H), 5.30 (m, 2H), 4.74 (s, 1H), 4.60 (m, 2H), 4.41-4.31(m, 3H), 3.92 (m, 1H), 3.65 (m, 1H), 1.35 (d, J=6 Hz, 3H). ES⁺ MS: 629(M+1).

Example 24 2-(4-Morpholinyl)ethyl({[({[(3S,11aR)-8-({[(2,4-difluorophenyl)methyl]amino}carbonyl)-3-methyl-5,7-dioxo-2,3,5,7,11,11a-hexahydro[1,3]oxazolo[3,2-a]pyrido[1,2-d]pyrazin-6-yl]oxy}methyl)oxy]carbonyl}oxy)acetate

The title compound was prepared from({[({[(3S,11aR)-8-({[(2,4-difluorophenyl)methyl]amino}carbonyl)-3-methyl-5,7-dioxo-2,3,5,7,11,11a-hexahydro[1,3]oxazolo[3,2-a]pyrido[1,2-d]pyrazin-6-yl]oxy}methyl)oxy]carbonyl}oxy)acetic(78 mg, 0.145 mmol), 2-(4-morpholinyl)ethanol (0.02 mL, 0.145 mmol),DMAP (18 mg, 0.145 mmol), and DCC (45 mg, 0.218 mmol), using a similarprocess to that described in example 23. Purification reverse-phase hplcyielded the title compound as a white solid. ¹H NMR (CDCl₃) δ 10.19 (m,1H), 8.43 (s, 1H), 7.32 (m, 1H), 6.76 (m, 2H), 5.98 (d, J=6.4 Hz, 1H),5.76 (d, J=6.4 Hz, 1H), 5.30 (dd, J=10, 3.6 Hz, 1H), 4.68-4.50 (m, 6H),4.43-4.31 (m, 3H), 3.9-3.90 (m, 4H), 3.70-3.41 (m, 4H), 3.31 (m, 2H),2.93 (m, 2H), 1.35 (d, J=6 Hz, 3H). ES⁺ MS: 651 (M+1).

Example 25 2-(Dimethylamino)ethyl({[({[(3S,11aR)-8-({[(2,4-difluorophenyl)methyl]amino}carbonyl)-3-methyl-5,7-dioxo-2,3,5,7,11,11a-hexahydro[1,3]oxazolo[3,2-a]pyrido[1,2-d]pyrazin-6-yl]oxy}methyl)oxy]carbonyl}oxy)acetatehydrochloric acid salt

a) 2-(Dimethylamino)ethyl({[({[(3S,11aR)-8-({[(2,4-difluorophenyl)methyl]amino}carbonyl)-3-methyl-5,7-dioxo-2,3,5,7,11,11a-hexahydro[1,3]oxazolo[3,2-a]pyrido[1,2-d]pyrazin-6-yl]oxy}methyl)oxy]carbonyl}oxy)acetate.The title compound was prepared from({[({[(3S,11aR)-8-({[(2,4-difluorophenyl)methyl]amino}carbonyl)-3-methyl-5,7-dioxo-2,3,5,7,11,11a-hexahydro[1,3]oxazolo[3,2-a]pyrido[1,2-d]pyrazin-6-yl]oxy}methyl)oxy]carbonyl}oxy)acetic(77 mg, 0.144 mmol), 2-(dimethylamino)ethanol (0.01 mL, 0.144 mmol),DMAP (18 mg, 0.145 mmol), and DCC (45 mg, 0.218 mmol), using a similarprocess to that described in example 23. Purification by reverse-phasehplc yielded the title compound as a white solid trifluoroacetic acidsalt. Material isolated in this manner was combined, dissolved indichloromethane, washed with aqueous sodium bicarbonate, and dried oversodium sulfate to yield the title compound as a residue. ¹H NMR (CDCl₃)δ 10.18 (m, 1H), 8.42 (s, 1H), 7.30 (m, 1H), 6.78 (m, 2H), 5.95 (d,J=6.4 Hz, 1H), 5.82 (d, J=6.4 Hz, 1H), 5.29 (m, 1H), 4.63 (s, 2H), 4.55(m, 2H), 4.43-4.28 (m, 3H), 4.21 (m, 2H), 3.91 (m, 1H), 3.63 (m, 1H),2.55 (m, 2H), 2.24 (s, 6H), 1.34 (d, J=6.4 Hz, 3H).b) 2-(Dimethylamino)ethyl({[({[(3S,11aR)-8-({[(2,4-difluorophenyl)methyl]amino}carbonyl)-3-methyl-5,7-dioxo-2,3,5,7,11,11a-hexahydro[1,3]oxazolo[3,2-a]pyrido[1,2-d]pyrazin-6-yl]oxy}methyl)oxy]carbonyl}oxy)hydrochloric acid salt. The product prepared as described in step (a)above (173 mg, 0.239 mmol) was dissolved in dichloromethane, washed withsodium bicarbonate solution, and dried over sodium sulfate. This isolatewas dissolved in dioxane, cooled in an ice-water bath and HCl (0.24 mL,1 normal solution) was added and the reaction was stirred 15 minutes atambient temperature. The mixture was concentrated under reduced pressureand triturated with an ethyl acetate/dichloromethane mixture and thesolid was collected by vacuum filtration. ¹H NMR (CDCl₃) δ 10.17 (m,1H), 8.46 (s, 1H), 7.31 (m, 1H), 6.78 (m, 2H), 5.94 (d, J=6.4 Hz, 1H),5.77 (d, J=6.4 Hz, 1H), 5.32 (m, 1H), 4.74-4.34 (m, 9H), 4.02 (m, 1H),3.65 (m, 1H), 3.39 (m, 2H), 2.82 (s, 6H), 1.34 (d, J=6 Hz, 3H). ES⁺ MS:609 (M+1).

Example 26 Rat Pharmacokinetics

Fasted male CD rats received the compound of Example 12 as an oralsuspension dose (5 mg parent equivalent/kg in 0.1%hydroxypropylmethylcellulose/0.1% Tween-80) administered via an oralgavage needle. Blood samples (0.2 mL each) were drawn from a surgicallyimplanted femoral vein cannula at timed intervals for 24 h followingdose administration; all samples were drawn using EDTA-treated syringes.Each blood sample was combined with 0.02 mL of a protease inhibitorsolution [e-amino-n-caproic acid, benzamide HCl, and4-(2-aminoethyl)benzenesulfonyl fluoride HCl in water] to inhibit exvivo conversion of prodrug to parent, vortexed to mix, and centrifuged(4000×g, 4° C., 20 min) to harvest plasma. Prodrug and parentconcentrations in plasma samples were quantitated by LC/MS/MS analysis.Area under the plasma concentration-time curve was estimated usingnoncompartmental analysis methods (WinNonlin Professional 4.1)

The invention claimed is:
 1. A compound of formula P-3


2. A compound of formula P-4